Connectivity Relation between axon terminal synapses and dendrites

With regards to the synapses between axon terminals and dendrites, what is the relation between a given neuron's axon terminals and its neighbouring neurons' dendrites?

  1. Does each axon synapse on only a single dendritic spine from another neuron, whereby all other connections that axon makes are with distinct neurons, or
  2. Can multiple axon terminals from a given neuron end up connecting to a single neuron via multiple dendritic spines?

Synapses are pretty much one-to-one

Here's some EM pictures of synapses, from Wikimedia commons:

You should gather from these images that these are super organized structures. There's a dense, dense gathering of cellular machinery at the synapse that creates a dark electron-dense region shown by the arrows. There's no room for more than one cell to be directly involved in this area, it's one membrane closely coupled with another membrane. It's as if you put the palms of your two hands together.

Some neuromodulators (and sometimes traditional neurotransmitters) are not released synaptically, though, and are just dumped into the extracellular space from where they diffuse in to the cleft or bind outside the synaptic region.

There can be multiple connections between two given cells

Though a synapse is a one-to-one connection, axons make multiple synaptic contacts as do dendrites. Though this can mean that cells receive and send input to 1000s of different cells, it's also very common for there to be multiple individual synapses between two specific cells.

For some examples, Tamas et al 1997 looked at synapses made from inhibitory interneurons to excitatory cells in visual cortex:

All presynaptic cells established multiple synaptic junctions on their postsynaptic target cells. A basket cell innervated a pyramidal cell via fifteen release sites; the numbers of synapses formed by three dendrite-targeting cells on pyramidal cells were seventeen and eight respectively, and three on a spiny stellate cell; the interaction between a double bouquet cell and a postsynaptic pyramidal cell was mediated by ten synaptic junctions.

Note in this paragraph they are literally talking about 5 specific pairs of cells, where they trace both cells in EM. This is an exhausting process. The presynaptic cells were one basket cell, three dendrite-targeting cells, and one double bouquet cell. The post-synaptic cells were all pyramidal cells except one was a spiny stellate cell. In the five pairs they found 15, 17, 8, 3, and 10 connections. Of course they could have missed some, too.

Tamas, G., Buhl, E. H., & Somogyi, P. (1997). Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neurone in the cat visual cortex. The Journal of physiology, 500(3), 715-738.

Synapses, (A Bit of) Biological Neural Networks – Part II

Synapses are the couplings between neurons, allowing signals to pass from one neuron to another. However, synapses are much more than mere relays: they play an important role in neural computation. The ongoing dramas of excitation and inhibition and of synaptic potentiation and depression give rise to your abilities to make decisions, learn, and remember. It’s amazing, really: collections of these microscopic junctions in your head can represent all sorts of things — your pet’s name, the layout of the New York subway system, how to ride a bike…

In this post, I give a rough overview of synapses: what they are, how they function, and how to model them. Specifically I will focus on synaptic transmission, with brief sections on short-term and long-term plasticity. Again, like before, nothing new is being said here, but I like to think the presentation is novel.


Brain is the central control system of the body. It is the main component of the central nervous system. It controls all the voluntary activities performed by a person. In addition, it also has control systems for the regulation of involuntary processes like respiratory rate, blood pressure, etc. It is also responsible for higher functions such as thought processing, memory formation, behavior, thinking, etc.

All these functions in the brain are performed by neurons. Neurons are the basic structural and functional units of the nervous system. different types of neurons are present in the brain. These neurons are connected via special links called synapses. In addition to the neurons, supporting cells called the neuroglial cells are also present in the brain.

In this article, we will talk about different types of neurons present in the brain, the structure, and functions of these neurons as well as the way they are connected. We will also discuss the role of glial cells in the brain. Besides, we will be discussing different types of synapses and their role in the brain.

The paper
S. Holler et al., “Structure and function of a neocortical synapse,” Nature, doi:10.1038/s41586-020-03134-2, 2021.

B rain cells use a language of neurotransmitters to pass messages to each other at junctions called synapses. A single neuron can have tens of thousands of synapses, allowing it to talk to thousands of other brain cells. These connections mediate information flow through the brain, and the plasticity of synapse strength is thought to underlie memory, learning, and other forms of cognition. Researchers have long suspected that synapses with greater surface areas are stronger, but have lacked experimental evidence for this, says Gregor Schuhknecht, a neuroscience postdoc at Harvard University.

To answer this question, Schuhknecht, then a graduate student at the Institute of Neuroinformatics at the University of Zurich and ETH Zurich, and his colleagues identified synapses between neuron pairs in the neocortex region of mouse brain slices. When an electrical impulse known as an action potential triggers the release of neurotransmitter-packed vesicles from a neuron’s axon terminal, these chemicals flow across the synapse and are recognized by receptors in the receiving neuron’s dendrite, which in turn may trigger an action potential in this cell. The team recorded the change in voltage of the receiving neuron with a tiny electrode to measure synapse strength and used electron microscopy to calculate synapse size. Sure enough, they found that synapses with a larger postsynaptic density area—the part
of the dendrite that houses neurotransmitter receptors—produced greater voltage changes.

Stephanie Rudolph, a neuroscientist at Albert Einstein College of Medicine who was not involved with the study, calls it a “technical tour de force” that confirms the relationship between synapse size and strength, a longstanding question in neuroscience.

Some researchers have measured neuron connectivity simply by counting the number of synapses between a neuron pair. The finding that larger synapses are stronger will allow connection strength to be assigned to a synapse based on its size, providing “a much more accurate picture of the connection,” says Schuhknecht. This should inform maps of the brain’s connectome that scientists are developing for fruit flies and mice, with the goal of understanding how information flows through the brain.

The strength of a synapse also depends on the number of neurotransmitter release sites in an axon terminal and the probability of a vesicle being released. Until now, most neuroscientists’ understanding was that synapses in the neocortex could release only a single vesicle of neurotransmitter per action potential, says Schuhknecht. But the research team calculated that the number of release sites exceeded the number of synapses between each neuron pair in the mouse brain slices, indicating that each synapse may be capable of releasing multiple vesicles. This means that the strength of synapses in the neocortex—the largest region in human brains—is more flexible than has been recognized.

“[This finding] profoundly alters the way we think about the predominant mode of synaptic transmission,” says Rudolph. “We can hypothesize that [multivesicular release] increases the ability of the brain to adapt to inside and outside challenges and allows a broader range of computational processing and information storage.”


We used in vivo time-lapse confocal microscopy to image synaptic sites in tectal neuron dendritic arbors and to examine mechanisms involved in the establishment of Xenopus retinotectal synaptic connectivity. Expression of DsRed2 and the postsynaptic density protein PSD95 tagged with GFP (PSD95-GFP) was used to visualize dendritic arbor morphology and postsynaptic specializations simultaneously in vivo(Fig. 1). PSD-95 associates with postsynaptic receptors and cytoskeletal elements, participates in synapse maturation, and has served as a marker for imaging postsynaptic specializations both in culture and in vivo(Ebihara et al., 2003 Marrs et al., 2001 Niell et al., 2004 Okabe et al., 2001). In Xenopus optic tectum, PSD95-GFP had a punctate distribution along individual DsRed2-labeled tectal neuron dendritic arbors(Fig. 1A-C). To confirm that PSD95-GFP was correctly targeted to postsynaptic sites in vivo, we compared PSD95-GFP distribution with that of an endogenous presynaptic protein. Immunostaining for the presynaptic plasma membrane protein SNAP-25 showed that, in the tectal neuropil, endogenous SNAP-25 is distributed in a punctate pattern that is complementary to that of PSD95-GFP punctate labeling(Fig. 1D-G) and of endogenous PSD-95 staining (Fig. 1H-J). Most of the PSD95-GFP puncta co-localized with endogenous SNAP-25 punctate staining (81.25±3.12%, 357 puncta analyzed from five neurons, one PSD95-GFP neuron per tadpole), indicating that PSD95-GFP targets to synaptic sites. Specific localization of PSD95-GFP at synapses was also confirmed ultrastructurally. Immunoelectron microscopy demonstrates that PSD95-GFP predominantly localized to the postsynaptic side of mature synaptic profiles in the tectal neuropil of stage 45 tadpoles(Fig. 2). Morphologically mature synapses with presynaptic terminals containing numerous synaptic vesicles and clearly defined postsynaptic specializations were immunopositive for GFP. In most immunopositive profiles (84.8%, or 28 out of 33 profiles analyzed from seven brains, one PSD95-GFP neuron per tadpole brain), the GFP immunoreactivity was localized at or near the postsynaptic density at the synapse (Fig. 2A-C). Therefore,these studies directly demonstrate that PSD95-GFP is recruited to synapses,and validate it as a marker to visualize postsynaptic sites in vivo.

PSD95-GFP specifically localizes to ultrastructurally identified synapses on tectal neuron dendrites. (A-C) The localization of PSD95-GFP was determined by examining the distribution of GFP immunoreactivity by electron microscopy. The electron photomicrographs show specific localization of GFP immunoreactivity as revealed by the silver-enhanced gold particles (open arrows) at postsynaptic terminals. Morphologically mature synapses (black arrows), containing presynaptic terminals with numerous synaptic vesicles (v) and clearly defined pre- and postsynaptic specializations are observed. The silver enhanced gold particles were directly localized to the postsynaptic membrane at the postsynaptic density (A-C), or were within 200 nm of the postsynaptic density (B). Scale bar: 200 nm.

PSD95-GFP specifically localizes to ultrastructurally identified synapses on tectal neuron dendrites. (A-C) The localization of PSD95-GFP was determined by examining the distribution of GFP immunoreactivity by electron microscopy. The electron photomicrographs show specific localization of GFP immunoreactivity as revealed by the silver-enhanced gold particles (open arrows) at postsynaptic terminals. Morphologically mature synapses (black arrows), containing presynaptic terminals with numerous synaptic vesicles (v) and clearly defined pre- and postsynaptic specializations are observed. The silver enhanced gold particles were directly localized to the postsynaptic membrane at the postsynaptic density (A-C), or were within 200 nm of the postsynaptic density (B). Scale bar: 200 nm.

Time-lapse imaging of PSD95-GFP puncta in individual DsRed2-labeled tectal neuron dendritic arbors was used to correlate dendritic arbor morphology with synapse formation and stabilization. Our previous studies show that BDNF significantly increases the number of presynaptic specializations and the complexity of RGC axon arbors in stage 45 Xenopus tadpoles within 4 hours of treatment (Alsina et al.,2001). At this stage, endogenous BDNF levels in the optic tectum are high (Cohen-Cory and Fraser,1994), and tectal neurons increase their complexity by an active remodeling of their dendritic arbors(Cline, 1998 Cline, 2001 Wu and Cline, 1998). Therefore, stage 45 tadpoles were imaged by confocal microscopy at 0, 4, 24 and 48 hours to determine potential effects of BDNF on tectal neurons. Microinjection of recombinant BDNF into the optic tectum did not alter the growth or morphology of tectal neuron dendritic arbors imaged at any of the observation time points when compared with controls(Fig. 3 and Fig. 4A,B). Similarly, BDNF did not influence dendritic arbor complexity of neurons in young tadpoles (prior to peak BDNF expression) imaged 48 hours post-treatment (see Materials and methods) nor the branching of tectal neurons imaged on a time-course of once every 2 hours (data not shown). By contrast, BDNF treatment significantly increased the number of PSD95-GFP-labeled postsynaptic specializations per individual arbor (Fig. 3 and Fig. 4C,D). Quantitative analysis of individual arbors demonstrates that the total number and density of PSD95-GFP puncta per tectal neuron dendritic arbor were significantly increased 24 hours after BDNF treatment when compared with controls(Fig. 4C,D). The difference in the number and density of PSD95-GFP puncta became more dramatic by 48 hours(Fig. 4C,D).

Our previous studies demonstrate a dual function for BDNF during the formation and stabilization of both synapses and axon branches in Xenopus RGC arbors (Alsina et al.,2001 Hu et al.,2005). Increasing BDNF within the tadpole optic tectum induces new axon branches and presynaptic specializations to be formed while decreasing endogenous BDNF induces the destabilization of both presynaptic sites and axon branches. These observations suggest that limiting amounts of BDNF dictate the extent of axon arbor growth and stabilization. Thus, to determine whether the effects of recombinant BDNF on tectal dendrites reflect the actions of endogenous BDNF, we decreased endogenous BDNF levels by injecting a BDNF function-blocking antibody into the optic tectum. As observed for recombinant BDNF, the anti-BDNF treatment did not alter dendritic branch number at any observation interval (4, 24 or 48 hours Fig. 3D). Total branch number was similar for tectal neurons in control, BDNF, and anti-BDNF treated tadpoles (Fig. 4A), indicating that dendritic branching was unaffected by alterations in BDNF signaling. However, neutralizing endogenous BDNF did limit the spatial extent of the dendritic arbor. Total dendritic arbor length remained constant in tectal neurons in anti-BDNF treated tadpoles throughout the 48-hour observation period (105.2±9% of time zero, 6 Fig. 4B), while in controls,total dendrite arbor length increased to 153.5±15% of its initial value by 48 hours (P≤0.05). Neutralizing endogenous BDNF with anti-BDNF had opposite effects on GFP-labeled postsynaptic specializations to those of recombinant BDNF, significantly decreasing the number of PSD95-GFP puncta in the tectal dendrites (Fig. 3D). The total number of PSD95-GFP puncta per tectal neuron was significantly lower than controls 24 hours after anti-BDNF treatment, an effect that became more pronounced by 48 hours (Fig. 4C). Because neutralization of endogenous BDNF influenced the length of the dendritic arbor and the number of PSD95-GFP puncta, when normalized, the number of postsynaptic specializations per unit arbor length(postsynaptic specialization density Fig. 4D) did not differ significantly from control, although the two parameters were affected independently. Time-lapse analysis revealed, however,that the decrease in the absolute number of PSD95-GFP puncta in the anti-BDNF-treated tadpoles resulted in a significant decrease in the density of postsynaptic specializations in branches that remained stable over time(Fig. 5). Thus, like treatment with recombinant BDNF, neutralizing endogenous BDNF within the optic tectum affected postsynaptic specialization number in tectal neuron dendritic arbors.

Detailed analysis of the localization and the lifetimes of individual PSD95-GFP puncta per dendritic arbor revealed that the effect of BDNF on synapse density was due to the selective addition of new postsynaptic specializations rather than stabilization of existing ones(Fig. 6). The BDNF-elicited increase in synapse addition occurred between 4 and 24 hours after treatment(Fig. 6B). Conversely, the anti-BDNF-elicited decrease in synapse number was the result of a reduced amount of newly added postsynaptic specializations. That is, significantly fewer PSD95-GFP puncta were formed by 48 hours following anti-BDNF treatment,a trend that was observed from 4 hours onwards(Fig. 6B). The proportion of PSD95-GFP puncta that remained stable in neurons in BDNF and in anti-BDNF treated tadpoles was similar to that of controls at all observation intervals(Fig. 6A). Together, our results demonstrate that alterations in tectal BDNF levels do not influence tectal neuron dendritic arbor morphology but rather influence synapse density by modulating synapse formation.

Proper function of the central nervous system (CNS) depends on the specificity of synaptic connections between cells of various types. Cellular and molecular mechanisms responsible for the establishment and refinement of these connections during development are the subject of an active area of research [1, 2, 3, 4, 5, 6]. However, it is unknown if the adult mammalian CNS can form new type-selective synapses following neural injury or disease. Here, we assess whether selective synaptic connections can be reestablished after circuit disruption in the adult mammalian retina. The stereotyped circuitry at the first synapse in the retina, as well as the relatively short distances new neurites must travel compared to other areas of the CNS, make the retina well suited to probing for synaptic specificity during circuit reassembly. Selective connections between short-wavelength sensitive cone photoreceptors (S-cones) and S-cone bipolar cells provides the foundation of the primordial blue-yellow vision, common to all mammals [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. We take advantage of the ground squirrel retina, which has a one-to-one S-cone-to-S-cone-bipolar-cell connection, to test if this connectivity can be reestablished following local photoreceptor loss [8, 19]. We find that after in vivo selective photoreceptor ablation, deafferented S-cone bipolar cells expand their dendritic trees. The new dendrites randomly explore the proper synaptic layer, bypass medium-wavelength sensitive cone photoreceptors (M-cones), and selectively synapse with S-cones. However, non-connected dendrites are not pruned back to resemble unperturbed S-cone bipolar cells. We show, for the first time, that circuit repair in the adult mammalian retina can recreate stereotypic selective wiring.

Present address: Section on Light and Circadian Rhythms, National Institute of Mental Health, 35 Convent Drive, Bethesda, MD 20892, USA


The nervous system of the common laboratory fly, Drosophila melanogaster, contains around 100,000 neurons, the same number as a lobster. This number compares to 75 million in the mouse and 300 million in the octopus. A human brain contains around 86 billion neurons. Despite these very different numbers, the nervous systems of these animals control many of the same behaviors&mdashfrom basic reflexes to more complicated behaviors like finding food and courting mates. The ability of neurons to communicate with each other as well as with other types of cells underlies all of these behaviors.

Most neurons share the same cellular components. But neurons are also highly specialized&mdashdifferent types of neurons have different sizes and shapes that relate to their functional roles.

Parts of a Neuron

Like other cells, each neuron has a cell body (or soma) that contains a nucleus, smooth and rough endoplasmic reticulum, Golgi apparatus, mitochondria, and other cellular components. Neurons also contain unique structures, illustrated in Figure (PageIndex<2>) for receiving and sending the electrical signals that make neuronal communication possible. Dendrites are tree-like structures that extend away from the cell body to receive messages from other neurons at specialized junctions called synapses . Although some neurons do not have any dendrites, some types of neurons have multiple dendrites. Dendrites can have small protrusions called dendritic spines, which further increase surface area for possible synaptic connections.

Once a signal is received by the dendrite, it then travels passively to the cell body. The cell body contains a specialized structure, the axon hillock that integrates signals from multiple synapses and serves as a junction between the cell body and an axon . An axon is a tube-like structure that propagates the integrated signal to specialized endings called axon terminals . These terminals in turn synapse on other neurons, muscle, or target organs. Chemicals released at axon terminals allow signals to be communicated to these other cells. Neurons usually have one or two axons, but some neurons, like amacrine cells in the retina, do not contain any axons. Some axons are covered with myelin , which acts as an insulator to minimize dissipation of the electrical signal as it travels down the axon, greatly increasing the speed on conduction. This insulation is important as the axon from a human motor neuron can be as long as a meter&mdashfrom the base of the spine to the toes. The myelin sheath is not actually part of the neuron. Myelin is produced by glial cells. Along the axon there are periodic gaps in the myelin sheath. These gaps are called nodes of Ranvier and are sites where the signal is &ldquorecharged&rdquo as it travels along the axon.

It is important to note that a single neuron does not act alone&mdashneuronal communication depends on the connections that neurons make with one another (as well as with other cells, like muscle cells). Dendrites from a single neuron may receive synaptic contact from many other neurons. For example, dendrites from a Purkinje cell in the cerebellum are thought to receive contact from as many as 200,000 other neurons.

Figure (PageIndex<1>): Neurons contain organelles common to many other cells, such as a nucleus and mitochondria. They also have more specialized structures, including dendrites and axons.

Which of the following statements is false?

  1. The soma is the cell body of a nerve cell.
  2. Myelin sheath provides an insulating layer to the dendrites.
  3. Axons carry the signal from the soma to the target.
  4. Dendrites carry the signal to the soma.

Types of Neurons

There are different types of neurons, and the functional role of a given neuron is intimately dependent on its structure. There is an amazing diversity of neuron shapes and sizes found in different parts of the nervous system (and across species), as illustrated by the neurons shown in Figure (PageIndex<3>).

Figure (PageIndex<3>): There is great diversity in the size and shape of neurons throughout the nervous system. Examples include (a) a pyramidal cell from the cerebral cortex, (b) a Purkinje cell from the cerebellar cortex, and (c) olfactory cells from the olfactory epithelium and olfactory bulb.

While there are many defined neuron cell subtypes, neurons are broadly divided into four basic types: unipolar, bipolar, multipolar, and pseudounipolar. Figure (PageIndex<4>) illustrates these four basic neuron types. Unipolar neurons have only one structure that extends away from the soma. These neurons are not found in vertebrates but are found in insects where they stimulate muscles or glands. A bipolar neuron has one axon and one dendrite extending from the soma. An example of a bipolar neuron is a retinal bipolar cell, which receives signals from photoreceptor cells that are sensitive to light and transmits these signals to ganglion cells that carry the signal to the brain. Multipolar neurons are the most common type of neuron. Each multipolar neuron contains one axon and multiple dendrites. Multipolar neurons can be found in the central nervous system (brain and spinal cord). An example of a multipolar neuron is a Purkinje cell in the cerebellum, which has many branching dendrites but only one axon. Pseudounipolar cells share characteristics with both unipolar and bipolar cells. A pseudounipolar cell has a single process that extends from the soma, like a unipolar cell, but this process later branches into two distinct structures, like a bipolar cell. Most sensory neurons are pseudounipolar and have an axon that branches into two extensions: one connected to dendrites that receive sensory information and another that transmits this information to the spinal cord.

Figure (PageIndex<4>): Neurons are broadly divided into four main types based on the number and placement of axons: (1) unipolar, (2) bipolar, (3) multipolar, and (4) pseudounipolar.

Everyday Connection: Neurogenesis

At one time, scientists believed that people were born with all the neurons they would ever have. Research performed during the last few decades indicates that neurogenesis, the birth of new neurons, continues into adulthood. Neurogenesis was first discovered in songbirds that produce new neurons while learning songs. For mammals, new neurons also play an important role in learning: about 1000 new neurons develop in the hippocampus (a brain structure involved in learning and memory) each day. While most of the new neurons will die, researchers found that an increase in the number of surviving new neurons in the hippocampus correlated with how well rats learned a new task. Interestingly, both exercise and some antidepressant medications also promote neurogenesis in the hippocampus. Stress has the opposite effect. While neurogenesis is quite limited compared to regeneration in other tissues, research in this area may lead to new treatments for disorders such as Alzheimer&rsquos, stroke, and epilepsy.

How do scientists identify new neurons? A researcher can inject a compound called bromodeoxyuridine (BrdU) into the brain of an animal. While all cells will be exposed to BrdU, BrdU will only be incorporated into the DNA of newly generated cells that are in S phase. A technique called immunohistochemistry can be used to attach a fluorescent label to the incorporated BrdU, and a researcher can use fluorescent microscopy to visualize the presence of BrdU, and thus new neurons, in brain tissue. Figure (PageIndex<5>) is a micrograph which shows fluorescently labeled neurons in the hippocampus of a rat.

Figure (PageIndex<5>): This micrograph shows fluorescently labeled new neurons in a rat hippocampus. Cells that are actively dividing have bromodoxyuridine (BrdU) incorporated into their DNA and are labeled in red. Cells that express glial fibrillary acidic protein (GFAP) are labeled in green. Astrocytes, but not neurons, express GFAP. Thus, cells that are labeled both red and green are actively dividing astrocytes, whereas cells labeled red only are actively dividing neurons. (credit: modification of work by Dr. Maryam Faiz, et. al., University of Barcelona scale-bar data from Matt Russell)

This site contains more information about neurogenesis, including an interactive laboratory simulation and a video that explains how BrdU labels new cells.

183 How Neurons Communicate

By the end of this section, you will be able to do the following:

  • Describe the basis of the resting membrane potential
  • Explain the stages of an action potential and how action potentials are propagated
  • Explain the similarities and differences between chemical and electrical synapses
  • Describe long-term potentiation and long-term depression

All functions performed by the nervous system—from a simple motor reflex to more advanced functions like making a memory or a decision—require neurons to communicate with one another. While humans use words and body language to communicate, neurons use electrical and chemical signals. Just like a person in a committee, one neuron usually receives and synthesizes messages from multiple other neurons before “making the decision” to send the message on to other neurons.

Nerve Impulse Transmission within a Neuron

For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or ‘resting’ membrane charge.

Neuronal Charged Membranes

The lipid bilayer membrane that surrounds a neuron is impermeable to charged molecules or ions. To enter or exit the neuron, ions must pass through special proteins called ion channels that span the membrane. Ion channels have different configurations: open, closed, and inactive, as illustrated in (Figure). Some ion channels need to be activated in order to open and allow ions to pass into or out of the cell. These ion channels are sensitive to the environment and can change their shape accordingly. Ion channels that change their structure in response to voltage changes are called voltage-gated ion channels. Voltage-gated ion channels regulate the relative concentrations of different ions inside and outside the cell. The difference in total charge between the inside and outside of the cell is called the membrane potential .

This video discusses the basis of the resting membrane potential.

Resting Membrane Potential

A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell, as shown in (Figure). The difference in the number of positively charged potassium ions (K + ) inside and outside the cell dominates the resting membrane potential ((Figure)). When the membrane is at rest, K + ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient. However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps brings two K + ions into the cell while removing three Na + ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid. It should be noted that chloride ions (Cl – ) tend to accumulate outside of the cell because they are repelled by negatively-charged proteins within the cytoplasm.

The resting membrane potential is a result of different concentrations inside and outside the cell.
Ion Concentration Inside and Outside Neurons
Ion Extracellular concentration (mM) Intracellular concentration (mM) Ratio outside/inside
Na + 145 12 12
K+ 4 155 0.026
Cl − 120 4 30
Organic anions (A−) 100

Action Potential

A neuron can receive input from other neurons and, if this input is strong enough, send the signal to downstream neurons. Transmission of a signal between neurons is generally carried by a chemical called a neurotransmitter. Transmission of a signal within a neuron (from dendrite to axon terminal) is carried by a brief reversal of the resting membrane potential called an action potential . When neurotransmitter molecules bind to receptors located on a neuron’s dendrites, ion channels open. At excitatory synapses, this opening allows positive ions to enter the neuron and results in depolarization of the membrane—a decrease in the difference in voltage between the inside and outside of the neuron. A stimulus from a sensory cell or another neuron depolarizes the target neuron to its threshold potential (-55 mV). Na + channels in the axon hillock open, allowing positive ions to enter the cell ((Figure) and (Figure)). Once the sodium channels open, the neuron completely depolarizes to a membrane potential of about +40 mV. Action potentials are considered an “all-or nothing” event, in that, once the threshold potential is reached, the neuron always completely depolarizes. Once depolarization is complete, the cell must now “reset” its membrane voltage back to the resting potential. To accomplish this, the Na + channels close and cannot be opened. This begins the neuron’s refractory period , in which it cannot produce another action potential because its sodium channels will not open. At the same time, voltage-gated K + channels open, allowing K + to leave the cell. As K + ions leave the cell, the membrane potential once again becomes negative. The diffusion of K + out of the cell actually hyperpolarizes the cell, in that the membrane potential becomes more negative than the cell’s normal resting potential. At this point, the sodium channels will return to their resting state, meaning they are ready to open again if the membrane potential again exceeds the threshold potential. Eventually the extra K + ions diffuse out of the cell through the potassium leakage channels, bringing the cell from its hyperpolarized state, back to its resting membrane potential.

Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K + through voltage-gated K + channels. Which part of the action potential would you expect potassium channels to affect?

This video presents an overview of action potential.

Myelin and the Propagation of the Action Potential

For an action potential to communicate information to another neuron, it must travel along the axon and reach the axon terminals where it can initiate neurotransmitter release. The speed of conduction of an action potential along an axon is influenced by both the diameter of the axon and the axon’s resistance to current leak. Myelin acts as an insulator that prevents current from leaving the axon this increases the speed of action potential conduction. In demyelinating diseases like multiple sclerosis, action potential conduction slows because current leaks from previously insulated axon areas. The nodes of Ranvier, illustrated in (Figure) are gaps in the myelin sheath along the axon. These unmyelinated spaces are about one micrometer long and contain voltage-gated Na + and K + channels. Flow of ions through these channels, particularly the Na + channels, regenerates the action potential over and over again along the axon. This ‘jumping’ of the action potential from one node to the next is called saltatory conduction . If nodes of Ranvier were not present along an axon, the action potential would propagate very slowly since Na + and K + channels would have to continuously regenerate action potentials at every point along the axon instead of at specific points. Nodes of Ranvier also save energy for the neuron since the channels only need to be present at the nodes and not along the entire axon.

Synaptic Transmission

The synapse or “gap” is the place where information is transmitted from one neuron to another. Synapses usually form between axon terminals and dendritic spines, but this is not universally true. There are also axon-to-axon, dendrite-to-dendrite, and axon-to-cell body synapses. The neuron transmitting the signal is called the presynaptic neuron, and the neuron receiving the signal is called the postsynaptic neuron. Note that these designations are relative to a particular synapse—most neurons are both presynaptic and postsynaptic. There are two types of synapses: chemical and electrical.

Chemical Synapse

When an action potential reaches the axon terminal it depolarizes the membrane and opens voltage-gated Na + channels. Na + ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated Ca 2+ channels to open. Calcium ions entering the cell initiate a signaling cascade that causes small membrane-bound vesicles, called synaptic vesicles , containing neurotransmitter molecules to fuse with the presynaptic membrane. Synaptic vesicles are shown in (Figure), which is an image from a scanning electron microscope.

Fusion of a vesicle with the presynaptic membrane causes neurotransmitter to be released into the synaptic cleft , the extracellular space between the presynaptic and postsynaptic membranes, as illustrated in (Figure). The neurotransmitter diffuses across the synaptic cleft and binds to receptor proteins on the postsynaptic membrane.

The binding of a specific neurotransmitter causes particular ion channels, in this case ligand-gated channels, on the postsynaptic membrane to open. Neurotransmitters can either have excitatory or inhibitory effects on the postsynaptic membrane, as detailed in (Figure). For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na + channels to open. Na + enters the postsynaptic cell and causes the postsynaptic membrane to depolarize. This depolarization is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. Release of neurotransmitter at inhibitory synapses causes inhibitory postsynaptic potentials (IPSPs) , a hyperpolarization of the presynaptic membrane. For example, when the neurotransmitter GABA (gamma-aminobutyric acid) is released from a presynaptic neuron, it binds to and opens Cl – channels. Cl – ions enter the cell and hyperpolarizes the membrane, making the neuron less likely to fire an action potential.

Once neurotransmission has occurred, the neurotransmitter must be removed from the synaptic cleft so the postsynaptic membrane can “reset” and be ready to receive another signal. This can be accomplished in three ways: the neurotransmitter can diffuse away from the synaptic cleft, it can be degraded by enzymes in the synaptic cleft, or it can be recycled (sometimes called reuptake) by the presynaptic neuron. Several drugs act at this step of neurotransmission. For example, some drugs that are given to Alzheimer’s patients work by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine. This inhibition of the enzyme essentially increases neurotransmission at synapses that release acetylcholine. Once released, the acetylcholine stays in the cleft and can continually bind and unbind to postsynaptic receptors.

Neurotransmitter Function and Location
Neurotransmitter Example Location
Acetylcholine CNS and/or PNS
Biogenic amine Dopamine, serotonin, norepinephrine CNS and/or PNS
Amino acid Glycine, glutamate, aspartate, gamma aminobutyric acid CNS
Neuropeptide Substance P, endorphins CNS and/or PNS

Electrical Synapse

While electrical synapses are fewer in number than chemical synapses, they are found in all nervous systems and play important and unique roles. The mode of neurotransmission in electrical synapses is quite different from that in chemical synapses. In an electrical synapse, the presynaptic and postsynaptic membranes are very close together and are actually physically connected by channel proteins forming gap junctions. Gap junctions allow current to pass directly from one cell to the next. In addition to the ions that carry this current, other molecules, such as ATP, can diffuse through the large gap junction pores.

There are key differences between chemical and electrical synapses. Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is unidirectional. Signaling in electrical synapses, in contrast, is virtually instantaneous (which is important for synapses involved in key reflexes), and some electrical synapses are bidirectional. Electrical synapses are also more reliable as they are less likely to be blocked, and they are important for synchronizing the electrical activity of a group of neurons. For example, electrical synapses in the thalamus are thought to regulate slow-wave sleep, and disruption of these synapses can cause seizures.

Signal Summation

Sometimes a single EPSP is strong enough to induce an action potential in the postsynaptic neuron, but often multiple presynaptic inputs must create EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential. This process is called summation and occurs at the axon hillock, as illustrated in (Figure). Additionally, one neuron often has inputs from many presynaptic neurons—some excitatory and some inhibitory—so IPSPs can cancel out EPSPs and vice versa. It is the net change in postsynaptic membrane voltage that determines whether the postsynaptic cell has reached its threshold of excitation needed to fire an action potential. Together, synaptic summation and the threshold for excitation act as a filter so that random “noise” in the system is not transmitted as important information.

Brain-computer interface
Amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s Disease) is a neurological disease characterized by the degeneration of the motor neurons that control voluntary movements. The disease begins with muscle weakening and lack of coordination and eventually destroys the neurons that control speech, breathing, and swallowing in the end, the disease can lead to paralysis. At that point, patients require assistance from machines to be able to breathe and to communicate. Several special technologies have been developed to allow “locked-in” patients to communicate with the rest of the world. One technology, for example, allows patients to type out sentences by twitching their cheek. These sentences can then be read aloud by a computer.

A relatively new line of research for helping paralyzed patients, including those with ALS, to communicate and retain a degree of self-sufficiency is called brain-computer interface (BCI) technology and is illustrated in (Figure). This technology sounds like something out of science fiction: it allows paralyzed patients to control a computer using only their thoughts. There are several forms of BCI. Some forms use EEG recordings from electrodes taped onto the skull. These recordings contain information from large populations of neurons that can be decoded by a computer. Other forms of BCI require the implantation of an array of electrodes smaller than a postage stamp in the arm and hand area of the motor cortex. This form of BCI, while more invasive, is very powerful as each electrode can record actual action potentials from one or more neurons. These signals are then sent to a computer, which has been trained to decode the signal and feed it to a tool—such as a cursor on a computer screen. This means that a patient with ALS can use e-mail, read the Internet, and communicate with others by thinking of moving his or her hand or arm (even though the paralyzed patient cannot make that bodily movement). Recent advances have allowed a paralyzed locked-in patient who suffered a stroke 15 years ago to control a robotic arm and even to feed herself coffee using BCI technology.

Despite the amazing advancements in BCI technology, it also has limitations. The technology can require many hours of training and long periods of intense concentration for the patient it can also require brain surgery to implant the devices.

Watch this video in which a paralyzed woman uses a brain-controlled robotic arm to bring a drink to her mouth, among other images of brain-computer interface technology in action.

Synaptic Plasticity

Synapses are not static structures. They can be weakened or strengthened. They can be broken, and new synapses can be made. Synaptic plasticity allows for these changes, which are all needed for a functioning nervous system. In fact, synaptic plasticity is the basis of learning and memory. Two processes in particular, long-term potentiation (LTP) and long-term depression (LTD) are important forms of synaptic plasticity that occur in synapses in the hippocampus, a brain region that is involved in storing memories.

Long-term Potentiation (LTP)

Long-term potentiation (LTP) is a persistent strengthening of a synaptic connection. LTP is based on the Hebbian principle: cells that fire together wire together. There are various mechanisms, none fully understood, behind the synaptic strengthening seen with LTP. One known mechanism involves a type of postsynaptic glutamate receptor, called NMDA (N-Methyl-D-aspartate) receptors, shown in (Figure). These receptors are normally blocked by magnesium ions however, when the postsynaptic neuron is depolarized by multiple presynaptic inputs in quick succession (either from one neuron or multiple neurons), the magnesium ions are forced out allowing Ca ions to pass into the postsynaptic cell. Next, Ca 2+ ions entering the cell initiate a signaling cascade that causes a different type of glutamate receptor, called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, to be inserted into the postsynaptic membrane, since activated AMPA receptors allow positive ions to enter the cell. So, the next time glutamate is released from the presynaptic membrane, it will have a larger excitatory effect (EPSP) on the postsynaptic cell because the binding of glutamate to these AMPA receptors will allow more positive ions into the cell. The insertion of additional AMPA receptors strengthens the synapse and means that the postsynaptic neuron is more likely to fire in response to presynaptic neurotransmitter release. Some drugs of abuse co-opt the LTP pathway, and this synaptic strengthening can lead to addiction.

Long-term Depression (LTD)

Long-term depression (LTD) is essentially the reverse of LTP: it is a long-term weakening of a synaptic connection. One mechanism known to cause LTD also involves AMPA receptors. In this situation, calcium that enters through NMDA receptors initiates a different signaling cascade, which results in the removal of AMPA receptors from the postsynaptic membrane, as illustrated in (Figure). The decrease in AMPA receptors in the membrane makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron. While it may seem counterintuitive, LTD may be just as important for learning and memory as LTP. The weakening and pruning of unused synapses allows for unimportant connections to be lost and makes the synapses that have undergone LTP that much stronger by comparison.

Section Summary

Neurons have charged membranes because there are different concentrations of ions inside and outside of the cell. Voltage-gated ion channels control the movement of ions into and out of a neuron. When a neuronal membrane is depolarized to at least the threshold of excitation, an action potential is fired. The action potential is then propagated along a myelinated axon to the axon terminals. In a chemical synapse, the action potential causes release of neurotransmitter molecules into the synaptic cleft. Through binding to postsynaptic receptors, the neurotransmitter can cause excitatory or inhibitory postsynaptic potentials by depolarizing or hyperpolarizing, respectively, the postsynaptic membrane. In electrical synapses, the action potential is directly communicated to the postsynaptic cell through gap junctions—large channel proteins that connect the pre-and postsynaptic membranes. Synapses are not static structures and can be strengthened and weakened. Two mechanisms of synaptic plasticity are long-term potentiation and long-term depression.

Visual Connection Questions

(Figure) Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K+ through voltage-gated K+ channels. Which part of the action potential would you expect potassium channels to affect?

(Figure) Potassium channel blockers slow the repolarization phase, but have no effect on depolarization.

Review Questions

For a neuron to fire an action potential, its membrane must reach ________.

  1. hyperpolarization
  2. the threshold of excitation
  3. the refractory period
  4. inhibitory postsynaptic potential

After an action potential, the opening of additional voltage-gated ________ channels and the inactivation of sodium channels, cause the membrane to return to its resting membrane potential.

What is the term for protein channels that connect two neurons at an electrical synapse?

  1. synaptic vesicles
  2. voltage-gated ion channels
  3. gap junction protein
  4. sodium-potassium exchange pumps

Which of the following molecules is not involved in the maintenance of the resting membrane potential?

Critical Thinking Questions

How does myelin aid propagation of an action potential along an axon? How do the nodes of Ranvier help this process?

Myelin prevents the leak of current from the axon. Nodes of Ranvier allow the action potential to be regenerated at specific points along the axon. They also save energy for the cell since voltage-gated ion channels and sodium-potassium transporters are not needed along myelinated portions of the axon.

What are the main steps in chemical neurotransmission?

An action potential travels along an axon until it depolarizes the membrane at an axon terminal. Depolarization of the membrane causes voltage-gated Ca 2+ channels to open and Ca 2+ to enter the cell. The intracellular calcium influx causes synaptic vesicles containing neurotransmitter to fuse with the presynaptic membrane. The neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane. Depending on the specific neurotransmitter and postsynaptic receptor, this action can cause positive (excitatory postsynaptic potential) or negative (inhibitory postsynaptic potential) ions to enter the cell.

Describe how long-term potentiation can lead to a nicotine addiction.

Long-term potentiation describes the process whereby exposure to a stimulus increases the likelihood that a neuron will depolarize in response to that stimulus in the future. Nicotine exposure causes long-term potentiation of neurons in the amygdala, and activates reward centers of the brain. As nicotine exposure continues, long-term potentiation reinforces the activation of the reward pathways in response to nicotine consumption.



Dendrites are tree-like extensions at the beginning of a neuron that help increase the surface area of the cell body. These tiny protrusions receive information from other neurons and transmit electrical stimulation to the soma. Dendrites are also covered with synapses.


  • Have many dendrites, or only one dendrit
  • Are short and highly branched
  • Transmit information to the cell body

Most neurons possess these branch-like extensions that extend outward away from the cell body. These dendrites then receive chemical signals from other neurons, which are then converted into electrical impulses that are transmitted toward the cell body.

Some neurons have very small, short dendrites, while other cells possess very long ones. The neurons of the central nervous systems have very long and complex dendrites that then receive signals from as many as a thousand other neurons.

If the electrical impulses transmitted inward toward the cell body are large enough, they will generate an action potential. This results in the signal being transmitted down the axon.​

The soma, or cell body, is where the signals from the dendrites are joined and passed on. The soma and the nucleus do not play an active role in the transmission of the neural signal. Instead, these two structures serve to maintain the cell and keep the neuron functional.  


  • Contains numerous organelles involved in a variety of cell functions
  • Contains a cell nucleus that produces RNA that directs the synthesis of proteins
  • Supports and maintains the functioning of the neuron

Think of the cell body as a small factory that fuels the neuron.

The soma produces the proteins that the other parts of the neuron, including the dendrites, axons, and synapses, need to function properly.

The support structures of the cell include mitochondria, which provide energy for the cell, and the Golgi apparatus, which packages products created by the cell and dispatches them to various locations inside and outside the cell.


Background and Purpose— Because the recovery process of axon terminals, synapses, and spine-dendrites in the ischemic penumbra of the cerebral cortex is obscure, we studied the temporal profile of these structures up to 12 weeks after the ischemic insult, using a gerbil model.

Methods— Stroke-positive animals were selected according to their stroke index score during the first 10-minute left carotid occlusion done twice with 5-hour interval. The animals were euthanized at various times after the second ischemic insult. Ultra-thin sections including the 2nd to 4th cortical layers were obtained from the neocortex coronally sectioned at the infundibular level, in which the penumbra appeared. We counted the number of synapses, spines and multiple synapse boutons, measured neurite thickness, and determined the percent volume of the axon terminals and spines by Weibel point counting method.

Results— The number of synapses, synaptic vesicles and spines and the total percent volume of the axon terminals and spines decreased until the 4th day. From 1 to 12 weeks after the ischemic insult, these values increased to or exceeded the control ones, and neuritic thickening and increase in number of multiple synapse boutons occurred.

Conclusions— In the ischemic penumbra, the above structures degenerated, with a reduction in their number and size, until 4 days and then recovered from 1 to 12 weeks after the ischemic insult.

Cerebral infarction develops rapidly after a large ischemic insult. Earlier we developed a model of temporary ischemia in which a focal infarction surrounded by a large penumbra was produced in the cerebral cortex of Mongolian gerbils by giving a threshold amount of ischemic insult to induce focal infarction. 1,2

Concerning the neuronal recovery, recent findings have revealed that synapses and their networks express a high degree of functional and structural plasticity. 3 Ultrastructural changes in the postsynaptic density in hippocampal CA-1 were investigated after temporary ischemia. 4–6 Degenerated boutons and multiple synapse boutons (MSBs) in this region were investigated by electron microscopy (EM) after temporary ischemia, 7–9 as well as after temporary hypoxia/hypoglycemia in hippocampal slices. 10 Changes in spines and dendrites were studied by time-lapse microscopy after temporary anoxia/hypoglycemia in cell culture, 11,12 by light microscopy (LMS) of Golgi stain-impregnated sections of the 3rd to 5th cortical layers of the cerebral cortex after temporary ischemia, 13 and by EM after temporary hypoxia/glycemia in hippocampal slice. 10 Changes in CA-1 dendrites after temporary ischemia were investigated by light microscopy of horseradish peroxidase-injected specimens, 14 by EM after temporary ischemia in CA-1, 15,16 and by EM of Golgi stain-impregnated cerebral cortex after temporary ischemia for 20 minutes. 17

Almost all of the above studies were performed in connection with delayed ischemia-induced injury to CA-1 neurons, and observations were made during a short period after ischemia. However, clinically, most patients show gradual recovery from behavioral dysfunctions after a stroke. The long-term integrated profile of axon terminals, synapses, spines, and dendrites during the recovery stage after an ischemic insult has remained obscure, especially in the ischemic penumbra of the cerebral cortex.

Because no functional recovery is anticipated in the infarction itself, 18–20 we aimed to elucidate neuronal remodeling process in the ischemic penumbra in which neuronal death progresses in a disseminated fashion, 2,18,20 by focusing on the temporal profiles of axon terminals, synapses, spines, and neurites.

Materials and Methods

Under anesthesia with 2% halothane, 70% nitrous oxide, and 30% oxygen, the left carotid artery of adult male Mongolian gerbils (60 to 80 g) was twice occluded with a Heifetz aneurismal clip for 10 minutes each time, with a 5-hour interval between the 2 occlusions, anesthesia was discontinued immediately after each cervical surgery, the animals soon became awake and moved spontaneously.

Ischemia-positive animals registering >13 points were selected based on the stroke index score determined during the first occlusion. 21 The gerbils were euthanized at various times, ie, at 5, 12, 24, 48-hour, 4 days, and 1, 5, 8, and 12 weeks after the ischemic insult. Anesthetization was followed by intracardiac perfusion with diluted fixative (1% paraformaldehyde, 1.25% glutaraldehyde in 0.1 mol/L cacodylate buffer) for 5 minutes, followed by perfusion with concentrated fixative (4% paraformaldehyde, 5% glutaraldehyde in 0.1 mol/L cacodylate buffer) for 20 minutes for EM (3 animals in each time group), or with 10% phosphate-buffered formaldehyde fixative for 30 minutes for LMS (5 animals in each time group).

In this model, after the restoration of blood flow, only ischemic penumbra with progressing disseminated selective neuronal necrosis (DSNN) appeared in the coronal face sectioned at the infundibular level (Face B) and focal infarction evolved among the DSNN in the coronal face sectioned at the chiasm (Face A). Ultra-thin sections including the 2nd to 4th cortical layers were prepared from the left cerebral cortex at the mid-point between the interhemispheric and rhinal fissures on Face B, penumbra >1 mm caudal to infarction edge. The sections were double stained with uranyl acetate and lead solution, and observed with an electron microscope (H9000, Hitachi). Paraffin sections of both faces were separately stained with hematoxylin-eosin (HE) or periodic acid fuchsin Schiff (PAS) or by Bodian silver impregnation or used for immunohistochemical detection of glial fibrillary acidic protein.

Placing 1.0 cm×1.0 cm quadratic lattices of points on 5000×2.67 times enlarged EM photographs, we measured the number of synapses (synapses: consist of the pre- and postsynaptic densities associated with their cytoplasmic faces, and the synaptic cleft between them) and spines (spines: an ovoid bulb that is filled with a fluffy material and connected to dendrite directly or by a stalk) in the neuropil in a 100-cm 2 area (56 μm 2 , by real size) by examining 1800±364 cm 2 in the neuropil of 3 animals in each time group. We determined the percent volume of the axon terminals (axon terminals: presynaptic expansion of the axon that contains synaptic vesicles and mitochondria) and spines by using the point counting method 22 in which the number of intersecting points touched by the axon terminals and/or spines were counted among 1000 to 15 000 points (counting number varied according to the equation of the relative error for different volumetric proportions) of the quadratic lattice in each time group. We measured the thickness of 194±38 neurites (neurites: axons and dendrites those contain microtubules, neurofilaments and mitochondria differentiation between them in transverse section is often difficult, especially in small ones) in each time group, as the maximal diameter perpendicular to their neurofilaments and/or microtubules. We also measured the percentage of MSBs by counting 327±38 synapses in each time group, all on the same EM pictures. The statistical differences between each of the time groups were analyzed by ANOVA, followed by Bonferroni-Dunn test. All data in the Table and Figure 6 were presented as average±SEM and a statistical difference was accepted at P<0.05 level.

Percent of MSBs Among Synapses


In the ischemic penumbra of the cerebral cortex in Face B, eosinophilic ischemic neurons (HE staining) appeared in disseminated fashion among the normal-looking neurons in the 2nd to 6th cortical layers by LMS, around 5 hours after the ischemic insult. Some of these eosinophilic cell bodies became remarkably shrunken and died during the period of 12 to 48 hours, which indicates DSNN (Figure 1A). The eosinophilic ischemic neurons were found by EM to be disseminated electron-dense dark neurons that increased in number during the period of 12 to 48 hours after the ischemic insult.

Figure 1. Light-microscopy of 2nd to 4th cortical layers of the cerebral cortex in Face B. A, Twenty-four hours after the ischemic insult, some of the eosinophilic ischemic neurons show marked shrinkage compared with the more normal-looking neurons, indicating disseminated selective neuronal necrosis. These abnormal neurons increased in number until day 2 to 3 postischemia (HE, Bar 31.3 μm). B, Eight weeks after the ischemic insult. The eosinophilic ghost cells of faintly formed cell bodies are reduced in size and are found in the 3rd cortical layer (PAS, Bar 12.5 μm).

From 4 days until 8 weeks, these condensed electron-dense dark neurons became fragmented into an accumulation of electron-dense granular fragments, which were observed by LMS as eosinophilic ghost cells of faintly formed cell bodies by HE and PAS staining (Figure 1B). During 2 to 12 weeks, these eosinophilic ghost cells accumulated in the 3rd and occasionally in the 5th cortical layer decreasing in size because of loss of their periphery (Figure 1B). In Face A, focal infarction evolved and developed among the DSNN from 12 hours to 4 days.

From 4 days to 12 weeks after the ischemic insult, the axon terminals of the surviving neurons were found being attached to the peripherally located electron-dense granular fragments and dendritic portions of the shrunken dark neurons. Some of these terminals appeared to have pinched off pieces of the dead neurons, and they bore a crust of the electron-dense granular fragments of the dead neurons (Figure 2A). Other axon terminals were found attached to the electron-dense thick neurites of dead neurons (Figure 2B). Some of the fragment-encrusted axon terminals were occasionally observed to have synapsed with the spines and neurites of the surviving neurons (Figure 3A). Some axons connected to the dying neurons showed globular and abnormal distensions of their terminals as seen by silver impregnation (Figure 4A). These structures appeared as degenerated axon by EM. The amplified degenerated axon contained degenerated mitochondria, laminated dense bodies, and irregularly located neurofilaments and microtubules the degenerated axon occasionally made synapses onto adjacent structures (inset of Figure 4A).

Figure 2. Electron microscopy of 3rd layer of the cerebral cortex in Face B, 1 week after the ischemic insult. A, The axon terminals of the surviving neurons make contact with the periphery of the accumulated fragments of electron-dense granules of dead neurons (DN). Some of them appeared to have pinched off pieces of the dead neurons, and are encrusted by the electron-dense granular fragments of the dead neurons (arrows). Bar 2.3 μm. B, Some axon terminals are found attached to the electron dense thick neurites of dead neurons (arrows). Bar 2.6 μm.

Figure 3. A, Electron microscopy of the 3rd cortical layer in Face B, 1 week after the ischemic insult. Some axon terminals encrusted by the electron-dense granular fragments of the dead neurons are occasionally observed to have made synapses with the spines and neurites of the surviving neurons (arrow). Bar 3.1 μm. B, Electron microscopy of 3rd cortical layer of the cerebral cortex in Face B, 12 weeks after the ischemic insult. MSBs with >2 spines synapsed (arrows) to 1 axon terminal (a). A widened spine(s) with multiple synapses on axon terminal (a) is seen. Bar 3.2 μm.

Figure 4. A, Light-microscopy. Four days after the ischemic insult, some axons attached to dying neurons show globular and abnormal distension of their terminals (arrow-heads). Bar 8.9 μm. Bodian’s silver impregnation. Inset: EM observation of the distended degenerated axon 3 weeks after the ischemic insult. It contains degenerated mitochondria, laminated dense bodies, and irregularly located neurofilaments and microtubules and has synapses along its wall (arrows). Bar 1.3 μm. B, Electron microscopy of the 3rd layer of the cerebral cortex in Face B, 2 weeks after the ischemic insult. These amplified degenerated axons (arrows) are observed around accumulations of the fragmented electron-dense granular pieces of the dead neurons (DN). Bar 0.6 μm.

Such axons were often observed around the accumulations of the fragmented electron-dense granular pieces of the dead neurons (Figure 4B).

By 12 weeks after the ischemic insult, neuritic shafts and their branches were remarkably thickened (Figure 5B) compared with those at day 4 (Figure 5A), and they made synapses with voluminously enlarged and occasionally sprouting polygonal axons terminals filled with synaptic vesicles (Figure 5B). MSBs 23 of the axons terminals (Figure 3B) increased in frequency compared with those of the control animals (Table).

Figure 5. Electron microscopy of the 3rd layer of the cerebral cortex in Face B. A, Four days after the ischemic insult. The volume of axon-terminals and spines has decreased with a decrease in frequency of synaptic vesicles, especially those close to the synapse (arrows). The thickness of degenerated neurites has decreased slightly compared with that of the control (arrowheads). Bar 1.5 μm. B, Twelve weeks after the ischemic insult. The neuritic shafts and their branches are remarkably thickened (arrowheads) and make synapses with voluminously enlarged and occasionally sprouting polygonal axon terminals filled with synaptic vesicles (arrows). Bar 1.5 μm.

The percent volume of the total axon terminals (Figure 6A) and spines (Figure 6B) in the neuropil decreased drastically to 30.9% and 24.8%, respectively, of the control value at that time after the ischemic insult, with a decrease in frequency of synaptic vesicles especially those close to the synapses (Figure 5A). The number of synapses also decreased to 73.5% of the control value at 4 days, after a temporary increase up to 135% at 5 hours after the ischemic insult (Figure 6A). The number of spines also decreased to 35.8% of the control value (Figure 6B), by 4 days. From 1 to 12 weeks after the ischemic insult, the percent volume of the total axon terminals (Figure 6A) and the percent volume of the total spines (Figure 6B) increased, being 162.8% and 86.7%, respectively, of the control value at 12 weeks. The number of synapses (Figure 6A) and spines (Figure 6B) also rose, becoming 113.2% and 91.9%, respectively, of it at that time.

Figure 6. A, Time course of percent volume of axon terminals and number of synapses in the neuropil at various time after ischemic insult. B, Time course of percent volume and number of spines in the neuropil at various time post ischemia. C, Time course by scatter graph (upper) and average thickness (lower) of neurites in the neuropil after the ischemic insult. a Compared with control b compared with 4 days *P<0.001, †P<0.05.

The average thickness of neurites in the neuropil of the control animals were 0.607 μm. This value was unchanged at 0.587 μm at day 4, 0.604 μm at 1 week, and 0.665 μm at 8 weeks, and increased to 0.934 μm at 12 weeks after the ischemic insult (Figure 6C).


In the neuropils of the ischemic penumbra in the cerebral cortex, we found a marked decrease in the number of the synapses and volume of the axon terminals from 5 hours to 4 days after the ischemic insult, along with a decrease in the number of synaptic vesicles. These changes may be attributed to a demolished synaptic neurotransmission attributable to calcium-dependent neuronal hyperexcitation 4–6 and could be reduced by NMDA (N-methyl- d -asparate) receptor antagonists as was reported in a morphological study recording excitatory postsynaptic potential from hippocampal slice cultures subjected to brief anoxia-hypoglycemia. 10

Almost in accordance with our present study, the LMS study of Golgi silver impregnated spine and dendrites showed that the number of spines and thickness of dendrites decreased maximally in 4 to 7 days after the temporary ischemia and recovered around 5 weeks in the 2nd to 3rd cortical layers of the rat cerebral cortex. 13 Earlier studies on cultured neurons showed a decreased spine number and segmental dendritic beading after temporary hypoxia/hypoglycemia followed by recovery, 11,12 and a LMS study using horseradish protein injection showed beading of dendrites in the CA-1 of the hippocampus after temporary ischemia. 14 Also an EM study on the CA-1 showed degeneration and shrinkage of dendrite around 3 to 4 days after temporary ischemia. 15–17 In the present study, we found that the neurites degenerated around 4 days and that their thickness increased, in association with the recovery to normal of the number and percent volume of spines, at 12 weeks after the insult.

From 1 to 12 weeks after the ischemic insult, we found that the synaptic number increased gradually in association with an increase in the volume of axon terminals showing sprouting. The present study also showed an increase in the number of the MSBs from 8 to 12 weeks after the ischemic insult, which increase was associated with one in the number and volume of axon terminals and spines. The MSBs represent 2 independent dendritic spines contacting the same axon terminal. 23 One spine branched to make synapses at >2 portions of 1 axon terminal is considered to facilitate neurotransmission. 10 In another study, there was an increase in the number of MSBs in CA-1, paralleling the marked increase in the number of synaptic vesicles after temporary ischemia 7 and after temporary hypoxia/hypoglycemia in hippocampal slices. 10

From 4 days to 12 weeks after the ischemic insult, some axons attached to the dying neurons showed an abnormal distension of their terminals, which contained degenerated mitochondria, laminated dense bodies, and irregularly located neurofilaments and microtubules (degenerated axon). 8,9 They were frequently observed around accumulations of the electron-dense granular fragments of the dead neurons.

Some axon terminals encrusted with the electron-dense granular fragments of the dead neurons became connected to the spines and neurites of the surviving neurons. These axon terminals, previously attached to the dying and/or dead neurons, seemed to become newly connected to the spines and to the thickened dendrites of the surviving neurons associated with synaptogenesis in the neuropil. 24 However, it could also be that some of these axon terminals were originally contacting more than one dendrites or spines.

Clinically, most stroke survivors show recovery from behavioral dysfunctions. The short-term recovery may be attributable to the resolution of brain edema. A more gradual recovery, promoted by exercise for rehabilitation, may be attributed to the anatomical and functional recovery of the penumbra. Stroemer 24 reported behavioral recovery after neocortical infarction in rats, which recovery was associated with neuronal sprouting followed by synapto-genesis, as demonstrated by immunohistochemical staining for GAP-43, a growth-associated protein expressed on axonal growth cones, and for synaptophysin. Functional remodeling of the cerebral cortex remote from the infarction was detected by intracortical microstimulation mapping of the hand of the squirrel monkey. 25,26

Activation of the complement system was shown to promote neuronal survival and tissue remodeling. 27 Postischemic treatment with brain-derived neurotrophic factor and physically exercised animals had better functional motor recovery, attributable to induction of widespread neuronal remodeling, as demonstrated by MAP1B and synaptophysin expression. 19 Clinical introduction of novel agents and functional methods to promote synaptogenesis and neuronal networks in the iscehmic penumbra, is highly anticipated.


In the penumbra around a focal infarction of the cerebral cortex, synapses, synaptic vesicles, axon terminals, spines degenerated, with a reduction in their number and size, until 4 days and then recovered from 1 to 12 weeks after the ischemic insult.

Neuroscience For Kids

Neurons have specialized projections called dendrites and axons. Dendrites bring information to the cell body and axons take information away from the cell body.

Information from one neuron flows to another neuron across a synapse. The synapse contains a small gap separating neurons. The synapse consists of:

  1. a presynaptic ending that contains neurotransmitters, mitochondria and other cell organelles
  2. a postsynaptic ending that contains receptor sites for neurotransmitters
  3. a synaptic cleft or space between the presynaptic and postsynaptic endings.

Electrical Trigger for Neurotransmission

For communication between neurons to occur, an electrical impulse must travel down an axon to the synaptic terminal.

Neurotransmitter Mobilization and Release

At the synaptic terminal (the presynaptic ending), an electrical impulse will trigger the migration of vesicles (the red dots in the figure to the left) containing neurotransmitters toward the presynaptic membrane. The vesicle membrane will fuse with the presynaptic membrane releasing the neurotransmitters into the synaptic cleft. Until recently, it was thought that a neuron produced and released only one type of neurotransmitter. This was called "Dale's Law." However, there is now evidence that neurons can contain and release more than one kind of neurotransmitter.

Diffusion of Neurotransmitters Across the Synaptic Cleft

The neurotransmitter molecules then diffuse across the synaptic cleft where they can bind with receptor sites on the postsynaptic ending to influence the electrical response in the postsynaptic neuron. In the figure on the right, the postsynaptic ending is a dendrite (axodendritic synapse), but synapses can occur on axons (axoaxonic synapse) and cell bodies (axosomatic synapse).

When a neurotransmitter binds to a receptor on the postsynaptic side of the synapse, it changes the postsynaptic cell's excitability: it makes the postsynaptic cell either more or less likely to fire an action potential. If the number of excitatory postsynaptic events is large enough, they will add to cause an action potential in the postsynaptic cell and a continuation of the "message."

Many psychoactive drugs and neurotoxins can change the properties of neurotransmitter release, neurotransmitter reuptake and the availability of receptor binding sites.

Types of Synapses

Happy 123th Birthday to the word "SYNAPSE." In 2020, the word "synapse" turned 123 years old. The word synapse was first used in a book called A Textbook of Physiology, part three: The Central Nervous System, by Michael Foster and assisted by Charles S. Sherrington, in 1897. It was probably Charles S. Sherrington who coined the term synapse. The word "synapse" is derived from the Greek words "syn" and "haptein" that mean "together" and "to clasp," respectively.

"You are your synapses. They are who you are."
--- Joseph LeDoux, 2002 (in Synaptic Self)

Play the Interactive Word Search Game on the neuron and neurotransmitters. Play an Outside Game to reinforce what you have learned about the synapse. Color the synapse online: Picture 1| Picture 2

Watch the video: Πώς μπορούμε να αναπτύξουμε νέους νευρώνες στον εγκέφαλο. TED (December 2021).