Hierarchical Brain

Synapse

A synapse is a junction or connection between two neurons in the brain that allows an electrical signal in the first neuron to be transmitted to the second neuron.

Neurons and synapses are the building blocks for the workings of the brain and the obvious components for the lowest level in my hierarchy of levels of description of the workings of the human brain. It is ability of synapses to flexibly change and therefore retain a memory of past activity, along with the coincidence detection ability of neurons, that provides the basis of this hierarchy.

This page first provides a high-level description of the characteristics and capabilities of the two types of synapses, electrical and chemical; at a lower level of detail, both types also make use of the movement of ions, and chemical synapses are dependent on the action of neurotransmitters. An understanding of the lower levels is not required for my hierarchical explanation of the workings of the brain.

Overview

• A synapse is found at a place where two neurons come very close to one another and either physically touch or have a very small gap between them, and it can then transmit an electrical signal from the first neuron to the second neuron.
• There are two types of synapses in the human brain, electrical and chemical (more details on each in the sections below).
  • At an electrical synapse, the membranes of two neurons touch each other, and there are channels within the synapse that directly connect the insides of both, so a signal can pass straight through. This type is ideal for fast communication of an electrical signal, but also the passing of other messenger molecules, with a small amount of flexibility.
  • At a chemical synapse, there is a small gap between two neurons, and an electrical signal in the first neuron is converted to a chemical signal to be passed between the neurons, and then back to an electrical signal in the second neuron. This type is ideal for slower communication with much more variety and flexibility.
• It is useful to establish four areas of terminology before further details are given:
  1. When talking about a particular synapse, the first neuron sending the signal is referred to as the “presynaptic neuron”, and the second neuron receiving the signal is referred to as the “postsynaptic neuron”.
  2. The electric “signal” in the presynaptic neuron is also described as an “action potential” or as the neuron “firing” - these three terms mean the same thing (the term “spike” is also sometimes used for an action potential, but I do not use this term).
  3. When an action potential in the presynaptic neuron arrives at a synapse, the synapse is said to be “activated”, and generally this is only time when a synapse is able to cause a change to the electric charge in the postsynaptic neuron, which may (or may not) contribute to whether or not the postsynaptic neuron raises an action potential. Electrical synapses, however, can transmit a signal without an action potential being generated (more details below).
  4. A synapse that has a positive effect on whether or not the postsynaptic neuron raises an action potential is called an “excitatory” synapse; one that has a negative effect is called an “inhibitory” synapse.
• A synapse is a one-to-one connector.
  • It creates a connection from one neuron to another neuron at just one place where the two touch or get very close.
  • The place where a synapse is formed is usually between an axon on the presynaptic neuron and a dendrite on the postsynaptic neuron, and the signal is transmitted from the axon to the dendrite.
  • However, there are many other less common configurations for synapses, such as from one neuron’s axon to another neuron’s cell body (which are mostly the inhibitory synapses), or even from one neuron’s axon back to its own dendrite¹, which is called an autapse.
  • It is certainly possible for two specific neurons to have more than one synapse between them in different places, but their actions will be relatively independent of each other.
• A synapse is generally a one-way connection and transmits an electrical signal in one direction only.
  • The reason for this is that chemical synapses are not symmetrical; they have the mechanisms for releasing neurotransmitter chemicals on one side and the mechanisms for detecting those chemicals on the other².
  • However, some electrical synapses (see below) transmit some signals in either direction.
  • Relatively recent research has shown that some chemical synapses can have a limited influences in the opposite direction, known as retrograde neurotransmission, but this is only an influence on the future reliability or strength of the synapse, it is not the same as an electrical signal being passed.
• Synapses can change in many different ways and over many different timescales ranging from milliseconds to years (see the section below on change over time for more details).
  • New synapses can be created and old ones can be removed.
  • Existing synapses can change their strength and/or reliability depending on previous activity. These changes alter the amount of influence that a synapse has on whether or not the postsynaptic neuron raises an action potential.
  • The action of a synapse can also be affected by the chemical environment in the cerebrospinal fluid outside the neuron, which is called neuromodulation. The neurotransmitter chemicals that cause this are released by other neurons or by glia.
  The requirement for flexibility is why the operation of synapses (particularly chemical synapses) is more complex than might be expected.
• Whether or not a neuron generates an action potential at any particular time is dependent on the voltage across the cell membrane at a particular place near the start of the axon of the neuron at that particular time (details on this are on the page about movement of ions - signal production). This in turn is dependent on the sum effect of all signals received from any synapses leading up to that time. The effective strength of those signals at the cell body can depend on many factors:
  1. The strength of an individual synapse connection, which, for a chemical synapse, is mainly affected by the number of receptors in that synapse (see neurotransmitters), as well as the amount of neurotransmitter released by the presynaptic neuron.
  2. The number of times an individual synapse is activated in the time period.
  3. The distance of a synapse in relation away from the cell body.
  4. How many excitatory (positive) and how many inhibitory (negative) synapses are activated in the time interval.
  Since an individual neuron can potentially have thousands of synapses, this means that the decision as to whether or not a neuron fires can be very complex (see neuron signals for more details).
• There are three basic functions of synapses that are required as part of level 1 of my hierarchical structure to fulfil the requirements of level 2 and above:
  1. A neuron may raise an action potential if it detects a coincidence of action potentials that arrive via two or more synapses.
     • Generally it takes many synapses to be activated within a short period of time to cause an action potential in the postsynaptic neuron.
     • There is a lot more detail on this on the page on neurons.
  2. The activation of a synapse can have a positive or negative effect, so that the postsynaptic neuron is then more or less likely to raise an action potential (this depends on the type of neurotransmitter chemicals used in a chemical synapse).
  3. The strength or reliability of a synapse can change in response to activations and the synapse therefore has a form of memory relating to previous activity. These changes are the main way in which learning happens in the brain.
  When looked at from a higher-level viewpoint, these three aspects together create functionality at the second level of my hierarchy that I call memory-enhanced coincidence detection and lateral inhibition.
• Looking further ahead to even higher levels of my hierarchical structure, many connections between many neurons can together form hierarchal networks that process incoming data and enable the creation and maintenance of representative structures that I call symbol schemas, and ultimately create intelligence, self-awareness and consciousness.
• To assist in explaining how the low-level functionality of neurons and synapses can deal with the many millions of possible coincidences that need to be dealt with by an active human brain, I have created the concept of a ABCD neuron, a much simplified model neuron that has two input synapses and one output synapse.
• Research into what synapses do and how they work has been going on for many years, and in a number of areas the low-level details are still not fully understood.

Electrical synapses

• An electrical synapse is a physical connection between two neurons where their membranes are joined by channels that can allow particles to pass directly from one neuron to the other.
  • This contact point is also called a gap junction.
    • There are some other examples of electrical interactions between two cells in the brain that are not gap junctions, the primary example being an ephapse⁴.
    • However, these are unusual and their effects are not yet fully understood, and nowadays they are not described as synapses⁵.
    • So, for my purposes, an electrical synapse is the same as a gap junction.
    • It is called a gap junction because the two sets of connecting proteins in each membrane hold the two membranes apart with a gap of about 4nm, whereas the gap between two neuron membranes that are not a synapse is normally at least 20nm.
  • A gap junction is a cluster of many channels that directly connect the insides of the two neurons.
    • Each channel consists of an assembly of proteins embedded within each of the two neuron membranes that join together, called a connexon.
    • Each connexon is made up of six proteins called connexins that form a ring to create the channel (see illustration).
    • There are many different connexins that have different functions, but only a few are believed to be found in the human brain; GJD2 or connexin-36 is one of the common ones.
  • The channels in an electrical synapse are around 1.5nm in diameter¹⁰, which is large compared to the channels created by most other transmembrane proteins.
    • This means that a gap junction allows not only electrically charged particles to flow directly from one neuron to another, but also other small signalling molecules and peptide proteins¹¹.
    • If an electrical synapse has voltage-gated channels, then ions would only be able to travel in one direction.
    • In fact, it has been found that most electrical synapses have some element of voltage-gating, but they are partially open all the time, which means that small ions can pass through all the time, but large ions and large signalling molecules are restricted to when there is sufficient voltage across the membrane at the synapse¹⁴.
  • There is evidence that electrical synapses and chemical synapses that are close to each other between the same pair of neurons can interact and influence one another, and it has also been found that electrical synapses are important for synchronising groups of neurons all firing at once, or in regular patterns^{18, 19}.
    • This might mean, for example, that electrical synapses may be created or enhanced when a nearby chemical synapse is consistently strengthened, so helping to create a group of neurons that all fire at once as an ensemble.
    • Groups of neurons that fire all at once have been given various names - see symbol schema - history for my review of this subject.
  • The passing of charged particles though an electrical synapse is covered in the movement of ions - synapse.

Chemical synapses

• A chemical synapse requires that the membranes of the two neurons do not touch each other but have a very small gap between them (see diagram at the top of this page).
  • The synapse converts the electrical signal from the presynaptic neuron into a chemical signal so that it can cross the boundary between the two - see neurotransmitters - release for more details.
  • It is then converted back to an electrical signal in the postsynaptic neuron - see the involvement of the movement of ions and neurotransmitters - reception for more details.
• There are many different neurotransmitters, and they can have different effects on the charge across the postsynaptic membrane - neurotransmitters - synthesis and neurotransmitters - reception give more details.

A comparison of the two types

• Both electrical and chemical synapses are able to pass on a signal from one neuron to another, but there are many differences between the two types.
  • Chemical synapses had in the past been thought to be by far the most common type in the human brain, with electrical synapses being found only in certain areas (see electrical synapses - effects).
    • However, in recent years, evidence has shown that electrical synapses are far more common than previously thought^{15, 20}.
    • It is now known that electrical synapses are more common than chemical synapses early in development, and play an important role in that development, but there are far more chemical synapses than electrical synapses in the adult human brain²¹.
  • Electrical synapses do not necessarily require an action potential: ions and other molecules can pass through at any time, whereas chemical synapses are not activated until an action potential reaches their site, and only then can they pass on a signal.
  • Chemical synapses are capable of increasing the signal strength, electrical synapses can only pass on a signal at the same strength, or less^{9, 13}.
  • It had been assumed that, because electrical synapses were simpler and had fewer variables, they were less flexible and exhibited less plasticity than chemical synapses, but evidence is mounting that this is not necessarily the case, and that electrical synapses also can change depending on previous activity¹⁷.
  • Similarly, it had been assumed that electrical synapses were less affected than chemical synapses by neuromodulators but evidence has shown that this may not be true^{16, 20}.
  • However, anaesthetics do not have so much of an effect on electrical synapses as on chemical synapses²².
  • Chemical synapses are obviously slower than electrical synapses because of the transitions that have to happen in a chemical synapse from an electric signal to a chemical signal and then back to an electric signal.
  • Chemical synapses only pass a signal in one direction, but most electrical synapses are two-way³ (see above for more details) .

Statistics

• The number of synapses in a human brain is huge, but, unlike the number of neurons, does vary significantly during a human lifetime.
  • The number of synapses in a human baby’s brain is estimated to be 1000 trillion (10¹⁵ or 1,000,000,000,000,000)²³.
  • During childhood, and into early adulthood, the main process of learning involves the pruning of synaptic connections, so an adult human brain has far less, probably around 100 trillion (10¹⁴) synapses²⁴.
  • Most neurons have many hundreds or even thousands of synapses where signals are received from many other neurons, and also have perhaps hundreds of synapses where signals are sent to many other neurons.
• A synapse is so small that it cannot be studied properly using traditional optical microscopes, but with the advent of electron microscopes and super-resolution optical microscopes much progress has been made²⁶.
  • The size of a typical chemical synapse is 0.5 to 2 micrometres²⁶ (a micrometre is a millionth of a metre or a thousandth of a millimetre; for comparison, the size of a bacteria is around 1-10 micrometres).
  • At a chemical synapse, the gap between two neurons is between 15 and 40 nanometres (a nanometre is a billionth of a meter or a millionth of a millimetre). The gap between the two neurons at an electrical synapse is 3.5nm⁶.
  • A synaptic vesicle that holds a typical small-molecule neurotransmitter is a sphere of 40nm diameter (see synaptic vesicle structure).
  • A typical chemical synapse can hold between 100 and 400 vesicles containing neurotransmitter molecules ready for release^{12, 26}.
• The voltage change that can be produced by one chemical synapse, otherwise known as the synaptic strength, or postsynaptic potential (PSP), can range from 0.4mV to 20mV (0.4 millivolts is 0.0004 volts, 20 millivolts is 0.02 volts).
• An electrical synapse can transmit ions and therefore a voltage from one neuron to another almost instantaneously. A chemical synapse takes a minimum of 0.3 milliseconds and the delay can be 1-5 milliseconds or longer^{7, 8}.

Change over time

• There are three main categories of changes in synapses that can affect signalling between neurons. These changes can happen over varying timescales ranging from milliseconds to many days.
  1. New synapses can be created (called synaptogenesis).
     • If the two neurons already have close contact, this can happen quite quickly, in as little as two hours^{27, 28, 29}. A new dendritic spine, which is the structure on a dendrite that contains a synapse, connects to a new axon terminal on a branch called a telodendron.
     • If new dendrites or axon branches need to grow to enable the two neurons to be close enough to create a new synapse, this process will clearly take some time, probably many hours or days.
  2. Existing synapse connections can be pruned (called synaptic pruning).
  3. Some research has shown that the growth of new synapses and the pruning of existing ones is prompted by the overall level of electrical activity within the neuron. This would back-up my claim in the introduction that the brain is “self-configuring and self-balancing” because it means that all neurons are always seeking to maintain a specific amount of activity³⁰.
  4. Existing synapses can be strengthened or weakened, or change in reliability. These changes can have a number of different underlying causes, and there have been many attempts at investigating and explaining them, and different terminology has been used. It is a very complex area, and is certainly not yet fully understood. I have tried to summarise the situation in the three factors in the next paragraph, but this is far from a complete picture.
• A synapse has a memory which is dependent on at least three factors, and these are categorised into two different timescales. Short-term changes are generally considered to act in a time interval of between tens of milliseconds to a few minutes, long-term changes can last many minutes, hours, or much longer.
  1. A synapse is strengthened or weakened for a short time dependent on the frequency of usage. This is usually called short-term plasticity. (Note that the word “plastic” is used in neuroscience to mean “changeable”, “malleable” or “flexible”; the general use of the word for the material that is used for food containers etc. tends to give the impression that plastic is hard and not very flexible.)³¹
     • A rapid sequence of activations of a synapse, caused by a rapid sequence of action potentials in the presynaptic neuron can cause more neurotransmitter to be released at a synapse.
     • On the other hand, too many rapid activations can cause the supply of neurotransmitter at that synapse to be exhausted, at least for a time.
  2. A synapse is strengthened when the postsynaptic neuron fires at the same time as the presynaptic neuron. This is called long-term potentiation (LTP).
     • The precise mechanisms behind LTP are not yet fully known, but there are thought to be many different factors, with different ones being more prevalent in different parts of the brain or for different types of neurons or neurotransmitters.
     • It is assumed that two important factors are an increase in the amount of neurotransmitter released by the presynaptic neuron, and an increase in the number of receptors for that neurotransmitter in the postsynaptic neuron.
     • A small number of exceptions have been found where coincident activations do not strengthen a synapse, or in some cases even weaken it.
  3. A synapse is weakened when it is not used or when there is no coincident activation of the presynaptic and postsynaptic neurons. This is called long-term depression (LTD).
     • Again, the exact mechanisms are complex and not yet fully understood.
     • Two likely factors are a decrease in the amount of neurotransmitter released by the presynaptic neuron, and a decrease in the density of receptors of the neurotransmitter in the postsynaptic neuron.
  See also activity-dependent plasticity for a good overview of the history of this area, and spike-timing-dependent plasticity and metaplasticity for further details.
• Synapses are also affected by neuromodulation. These are temporary changes that generally last from a few seconds up to many hours or even days. They are changes to the chemical constituents of the cerebrospinal fluid outside the neuron, so the change is (in theory) fully reversible.

Support

• The creation, pruning, and strengthening and weakening of synapses can all be influenced by the activity of glia, particular astrocytes.
  • Astrocytes make contact with many synapses, affecting their communication ability by regulating neurotransmission.
  • They are involved with the mopping up of neurotransmitters at synapses after they have been used.
  • They are also involved in the creation and removal of synapses.

Conclusions

• The summary at the very top of this page says: “A synapse is a junction or connection between two neurons in the brain that allows an electrical signal in the first neuron to be transmitted to the second neuron.” The high-level functionality of a synapse is easily stated, but the details of its workings are far more complex than might be expected from this statement.
  • The amount of complexity is shown by the fact that this page, although quite lengthy, still only gives an overview of the details of how synapses work.
  • If the sole function of a synapse was to pass on a signal, then an electrical synapse that simply allows ions to pass between two cells would be sufficient.
  • But most synapses do not simply pass on a signal. Their strength or reliability, which means the amount of influence they have on whether or not the postsynaptic neuron raises an action potential, can vary depending on previous activity. A simpler way of saying this is that their action depends on a memory of previous actions.
  • These changes to synapses are the basis of all knowledge and learning in the brain.
  • The action of a synapse can also depend on the environment external to the neuron, called neuromodulation. This is used for temporary but wide-ranging changes such as attention, sleep, importance and mood.
  • However, typically any one synapse will make only a small contribution to this decision as to whether the postsynaptic neuron raises an action potential, so changes to synapses that actually have an effect are always going to be cumulative and multiple.

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References For information on references, see structure of this website - references

1. ^ Autapse-induced multiple coherence resonance in single neurons and neuronal networks - Yilmaz, Ozer, Baysal and Perc 2016
   doi: 10.1038/srep30914 downloadable here or see GoogleScholar.
   First page, beginning of main text: “Autapse is an unfamiliar synapse, which happens between the axon and soma of the same neuron, and forms a time-delayed self-feedback mechanism. This special kind of synapses on the nervous system was firstly explored by Van der Loos and Glaser, and they called it as autapse, meaning the self-synapse. Thereafter, the existence of autapses in different brain regions was notified in various experimental studies by using different experimental techniques.”
2. ^ In Search of Memory - Kandel 2006 Norton & Company USA - see GoogleScholar.
   This very readable book by the Nobel prize winner is an autobiography, history and text book all in one.
   In chapter 2, page 69: “[In 1955] Sanford Palay and George Palade at the Rockefeller Institute used the electron microscope to demonstrate that in the vast majority of cases, a slight space - the synaptic cleft - separates the presynaptic terminal of one cell from the dendrite of another cell. Those new images also revealed that the synapse is asymmetrical, and that the machinery for releasing chemical transmitters, discovered much later, is located only in the presynaptic cell. This explains why information in a neural circuit flows in just one direction.”
3. ^ Electrical synapses, a personal perspective (or history) - Bennett 2000
   doi: 10.1016/S0165-0173(99)00065-X (no download available, although see GoogleScholar).
   Page 24, second column, first paragraph, under the heading “Electrical versus chemical”: “Chemical synapses are fundamentally unidirectional, but then most single synapses do not excite their postsynaptic targets in any case. Electrical synapses are fundamentally bidirectional, unless they are rectifying, and that may prove to be where they are most useful for mammals.”
4. ^ Ibid. Electrical synapses, a personal perspective (or history)
   Page 17, under the heading “An aside on 'ephapses' and other nomenclatural niceties”: . “Angelique Arvanitaki coined the term ephapse from the Greek to mean an apposition that is not quite so close as a synapse ... She used it to denote what she thought of as artificial synapses, which she made by laying one axon along side another where the 'action currents' generated during an impulse in one axon altered the excitability of the other axon. This terminology suggests that she thought synaptic transmission was electrical ... Ephapse then came to be used for incidental contacts in the nervous system, particularly where activity in one or more axons excited other axons.”
5. ^ Ibid. Electrical synapses, a personal perspective (or history)
   Page 17, first column, second paragraph, part of the Introduction: “One does not have to have been at Oxford to define a synapse as a specialized site of functional interaction between neurons, although Sherrington and Eccles (and I) were. By this definition gap junctions form one class of electrical synapse. Another kind of electrical synapse mediates short latency inhibition of the Mauthner cell of teleost fishes and possibly mammalian cerebellar Purkinje cells; this form of electrical transmission is not mediated by gap junctions, and involves different junctional specializations... In addition, there probably are electrical interactions that occur between closely apposed cells without obvious gap junctions or specializations other than the absence of interposed glia. Whether these sites are to be considered synapses, i.e., specialized, or ephapses, i.e., incidental or accidental sites of interaction, may become clear with greater knowledge of the developmental mechanisms. Without deciding on a name one can still describe the electrical interaction, which does indeed appear to be uniquely associated with the close appositions.”
6. ^ Principles of Neural Science - Fifth edition - Kandel et al. McGraw-Hill US 2012 - or see GoogleScholar.
   Page 178, Table 8-1 entitled “Distinguishing Properties of Electrical and Chemical Synapses” states that the distance between pre- and postsynaptic cell membranes is 4nm for electrical synapses and 20-40nm for chemical synapses.
   Page 184 under the heading “Chemical Synapses Can Amplify Signals”: “In fact, the separation between the two cells at a chemical synapse, the synaptic cleft, is usually wider (20-40 nm) than the nonsynaptic intercellular space (20 nm).”
   However, on the Wikipedia chemical synapse page, the section on relationship of chemical to electrical synapses says: “At gap junctions [electrical synapses], cells approach within about 3.5 nm of each other, rather than the 20 to 40 nm distance that separates cells at chemical synapses.”, referencing the earlier fourth edition of “Principles of Neural Science” from 2000 as well as another source from 2004.
7. ^ Ibid. Principles of Neural Science
   Page 178, Table 8-1 entitled “Distinguishing Properties of Electrical and Chemical Synapses” states that the synaptic delay is “virtually absent” for electrical synapses and “Significant: at least 0.3ms, usually 1-5ms or longer” for chemical synapses.
   Page 185, second paragraph: “These several steps account for the synaptic delay at chemical synapses, a delay that can be as short as 0.3ms but often lasts several milliseconds.”
8. ^ Ibid. Principles of Neural Science
   Pages 180, 2nd paragraph, under the heading “Electrical Synapses Provide Instantaneous Signal Transmission”: “At electrical synapses, the synaptic delay - the time between the presynaptic spike and the postsynaptic potential - is remarkably short. Such a short latency is not possible with chemical transmission, which requires several biochemical steps: release of a transmitter from the presynaptic neuron, diffusion of transmitter molecules to the postsynaptic cell, binding of transmitter to a specific receptor, and subsequent gating of ion channels... Only current passing directly from one cell to another can produce the near-instantaneous transmission observed at the giant motor synapse [an electrical synapse of the crayfish].”
9. ^ Ibid. Principles of Neural Science
   Pages 180, 3rd paragraph, under the heading “Electrical Synapses Provide Instantaneous Signal Transmission”: “Another feature of electrical transmission is that the change in potential of the postsynaptic cell is directly related to the size and shape of the change in potential of the presynaptic cell. Even when a weak subthreshold depolarizing current is injected into the presynaptic neuron, some current enters the postsynaptic cell and depolarizes it. In contrast, at a chemical synapse the current in the presynaptic cell must reach the threshold for an action potential before it can release transmitter and elicit a response in the postsynaptic cell.”
10. ^ Ibid. Principles of Neural Science
    Pages 180, end of second paragraph under the heading “Cells at an Electrical Synapse Are Connected by Gap-Junction Channels”: “The pore of the [gap junction] channel has a large diameter of approximately 1.5 nm, which permits inorganic ions and small organic molecules and experimental markers such as fluorescent dyes to pass between the two cells.”
11. ^ Ibid. Principles of Neural Science
    Page 184, first paragraph: “Gap junctions are also important in the mammalian brain, where the synchronous firing of electrically coupled inhibitory interneurons generates synchronous, high-frequency oscillations. In addition to providing speed or synchrony in neuronal signaling, electrical synapses also can transmit metabolic signals between cells. Because gap-junction channels are relatively large and nonselective, they conduct a variety of inorganic cations and anions, including the second messenger Ca²⁺, and even allow moderate-sized organic compounds (less than 1,000 Da molecular weight) - such as the second messengers inositol 1,4,5-trisphosphate (IP₃), cyclic adenosine monophosphate (cAMP), and even small peptides - to pass from one cell to the next.”
12. ^ Ibid. Principles of Neural Science
    Page 184, first paragraph, under the heading “Chemical Synapses Can Amplify Signals”: “At most chemical synapses transmitter is released from specialized swellings of the axon, the presynaptic terminals, which typically contain 100 to 200 synaptic vesicles, each of which is filled with several thousand molecules of the neurotransmitter.”
13. ^ Ibid. Principles of Neural Science
    Page 185, second paragraph, under the heading “Chemical Synapses Can Amplify Signals”: “Just one synaptic vesicle releases several thousand molecules of transmitter that together can open thousands of ion channels in the target cell. In this way a small presynaptic nerve terminal, which generates only a weak electrical current, can depolarize a large postsynaptic cell.”
14. ^ Function of the voltage gate of gap junction channels: Selective exclusion of molecules - Qu and Dahl 2021
    doi: 10.1073/pnas.022324499 downloadable here or see GoogleScholar.
    Abstract on first page: “Gap junction channels span the membranes of two adjacent cells and allow the gated transit of molecules as large as second messengers from cell to cell. ...Gap junction channels formed by most connexins are affected by transjunctional voltage. ...the activated voltage gate preferentially restricts the passage of larger ions,... while having little effect on the electrical coupling arising from the passage of small electrolytes. Thus, a conceivable physiological role of the voltage gate is to selectively restrict the passage of large molecules between cells while allowing electrical coupling.”
    
15. ^ Electrical synapses and their functional interactions with chemical synapses - Pereda 2014
    doi: 10.1038/nrn3708 downloadable here or see GoogleScholar.
    Start of conclusion, page 260: “Electrical synapses have proved to be more widespread in the mammalian brain than originally anticipated. Thus, networks of electrically and chemically coupled neurons are not restricted to invertebrates but seem to be a feature of all nervous systems. This realization emphasizes the need to further explore the functional properties of electrical synapses (of which we know significantly less than we do about chemical synapses) and their interactions with chemical synapses.”
16. ^ Ibid. Electrical synapses and their functional interactions with chemical synapses
    Page 254, second paragraph: End of page 252: “...like their chemical counterparts, electrical synapses are highly modifiable by the action of neuromodulators such as dopamine and are capable of activity-dependent plasticity.”
17. ^ Ibid. Electrical synapses and their functional interactions with chemical synapses
    Page 254, second paragraph: “...although chemical synapses seem to be structurally more complex and functionally dynamic, emerging evidence indicates that electrical synapses might be similarly complex, diverse and highly modifiable.”
18. ^ Ibid. Electrical synapses and their functional interactions with chemical synapses
    Page 255, last-but-one paragraph: “...the development of neural circuits in disparate nervous systems seems to rely critically on interactions between chemical and electrical synapses, which reciprocally and dynamically regulate the emergence of these two forms of transmission.”
19. ^ Electrical synapses: a dynamic signaling system that shapes the activity of neuronal networks - Hormuzdi, Filippov, Mitropoulou, Monyer and Bruzzone 2003
    doi: 10.1016/j.bbamem.2003.10.023 downloadable here or see GoogleScholar.
    Page 115, end of first paragraph: “...electrophysiological recordings have recently emphasized a key role for electrical synapses in synchronizing large neuronal ensembles at different frequency bands, which have been proposed to underlie a variety of cognitive processes, such as perception, memory, and learning. Electrical transmission should be viewed, therefore, as a complementary form of communication, not alternative to chemical signaling, with which it interacts.”
    
20. ^ ^ Bridging the Gap - The Ubiquity and Plasticity of Electrical Synapses - Winlow, Qazzaz and Johnson 2017
    downloadable here or see GoogleScholar.
    Abstract, second bullet point and following: “ES [Electrical Synapses] are ubiquitous, found in all multicellular animals... ...ES may be modulated and exhibit plasticity in addition to promoting synergy between coupled neurons according to the strength of coupling. Strong electrical coupling promotes synchronous activity while weak coupling may desynchronise coupled neurons. Chemical synapses may modulate ES conductances and may regulate the degree of coupling between neurons. Because ES act as low pass filters, prolonged spike after-hyperpolarisations can allow them to act as inhibitory connections, but modifications of conductances can allow them to act as high pass filters and there is gathering evidence that their gain can be modulated and is activity dependent. ES may be modulated by anaesthetics at clinically relevant concentrations and volatile anaesthetics can reduce coupling between strongly electrically coupled neurons in a dose dependent manner. This may prove to be important during anaesthesia, given the ubiquity of ES in the mammalian brain.”
21. ^ Foundations of Neuroscience - Open Edition - Henley (2021) downloadable here, Chapter 8 entitled “Synapse structure”
    Under the heading “Synapse types” and subheading “Electrical”, end of first paragraph (this text is not in the downloaded version, so must be a recent addition): “Electrical synapses play an important role in the development of the nervous system but are also present throughout the developed nervous system, although in much smaller numbers that chemical synapses.”
22. ^ Interaction of anaesthetics with electrical synapses - Johnston, Simon and Ramon 1980
    doi: 10.1038/286498a0 (download not available, although see GoogleScholar).
    End of abstract paragraph on page 498: “The effects of anaesthetics on electrical synapses (gap-junctions or nexus) have not previously been studied. ... We report here the effects of several anaesthetics on electronic coupling between nerve cells, and show that electrical synapses are less sensitive to most anaesthetics than are chemical synapses and axonal membranes.”
23. ^ Wikipedia article on Neurons at the end of the paragraph under the heading “Connectivity”, quoting article Do we have brain to spare? - Drachman 2005
    doi: 10.1212/01.WNL.0000166914.38327.BB (download not available, although see GoogleScholar).
    The Wikipedia article says: “It has been estimated that the brain of a three-year-old child has about 10¹⁵ synapses (1 quadrillion).” This is stated in a number of other places on the Internet, but I cannot find a definitive source for this figure. However, it seems like a reasonable estimate.
    The Drachman article, in the second sentence, says: “The cerebral cortex has about 0.15 quadrillion synapses - or about a trillion synapses per cubic centimeter of cortex.” 0.15 quadrillion equals 15x10¹³, but this is not the whole human brain, only the cerebral cortex, the outer part of the brain.
24. ^ The interplay between neurons and glia in synapse development and plasticity - Stogsdill and Eroglu 2018
    doi: 10.1016/j.conb.2016.09.016 downloadable here or see GoogleScholar.
    Page 1, Overview: “The mammalian brain is a complex organ comprised of numerous cell types and greater than 1 x 10¹⁴ synapses.”
25. ^ Livewired - David Eagleman, Canongate 2020
    Page 7: “...the total number of connections between the neurons in your head is in the hundred of trillions (around 0.2 quadrillion). To calibrate yourself, think of it this way: there are twenty times more connections in a cubic millimeter of cortical tissue that there are human beings on the entire planet.”
26. ^ ^ ^ The Decade of Super-Resolution Microscopy of the Presynapse - Nosov, Kahms and Klingauf 2020
    doi: 10.3389/fnsyn.2020.00032 downloadable here or see GoogleScholar.
    Start of abstract, page 1: “The presynaptic compartment of the chemical synapse is a small, yet extremely complex structure. Considering its size, most methods of optical microscopy are not able to resolve its nanoarchitecture and dynamics. Thus, its ultrastructure could only be studied by electron microscopy. In the last decade, new methods of optical superresolution microscopy have emerged allowing the study of cellular structures and processes at the nanometer scale.”
    Page 2, under the heading “The Synapse in the Electron Microscopic Picture”: “The classical chemical synapse in the vertebrate CNS has a size of 0.5 to 2μm and can harbor between 100 and 400 SVs in boutons of hippocampal pyramidal neurons.”
27. ^ Assembly of New Individual Excitatory Synapses: Time Course and Temporal Order of Synaptic Molecule Recruitment - Friedman, Bresler, Garner and Ziv 2000
    doi: 10.1016/S0896-6273(00)00009-X downloadable here or see GoogleScholar.
    End of summary on the first page: “...glutamatergic synapse assembly can occur within 1-2 hr after initial contact and that presynaptic differentiation may precede postsynaptic differentiation.”
    However, the conclusion on page 66 suggests that many new synapses may take longer to form than this, even where an axon is already touching a dendrite.
28. ^ Fundamental Neuroscience ed. Squire, Bloom, Spitzer, du Lac, Ghosh and Berg - Academic Press, Elsevier, Third edition 2008 or see GoogleScholar.
    Chapter 18 “Target selection, topographic maps, and synapse formation” - Burden, O’Leary and Scheiffele
    Page 427, first paragraph, under the heading “Synapse formation in the central nervous system” and subheading “The First Contact between Axons and Their Neuronal Targets”:
    “A second important realization from imaging studies has been that the assembly of synapses occurs very rapidly. The time required from initial contact to establishment of a functional synapse is only in the range of 1-2 hours, with the formation of a presynaptic terminal occurring in only 10-20 minutes and the recruitment of postsynaptic neurotransmitter receptors lagging somewhat behind. This rapid timecourse is plausible if one considers that most synaptic components are 'ready-to-go' before contact and primarily need to be redistributed in response to a cell surface signal.”
29. ^ Molecular mechanisms of CNS synaptogenesis - Garner, Zhai, Gundelfinger and Ziv 2002
    doi: 10.1016/S0166-2236(02)02152-5 downloadable here or see GoogleScholar.
    Page 244, second paragraph “On average, each of the 10¹¹ neurons in the human brain receives and makes [around] 10,000 synaptic contacts. These can be excitatory, inhibitory or modulatory in nature. The vast majority is excitatory and uses glutamate as a neurotransmitter. Inhibitory neurotransmission is mediated by glycine or GABA, whereas modulatory neurotransmission is mediated by, among others, noradrenaline, 5-HT, dopamine, ACh and neuropeptides. Although presynaptic boutons from any given neuron generally release transmitter of one type, neurons usually receive multiple forms of synaptic input, which can be excitatory, inhibitory or modulatory. As such, each postsynaptic cell is able to place the appropriate complement of transmitter receptors into the PSD [postsynaptic density, an electron-dense thickening] of each synapse type”
    Figure 2 on page 245 is titled “Synaptogenesis at CNS glutamatergic synapse” and it shows four complex steps that make up the process of creating a new synapse between an axon and a dendrite. It states that all four steps can take place within approximately 90 minutes.
30. ^ A Simple Rule for Dendritic Spine and Axonal Bouton Formation Can Account for Cortical Reorganization after Focal Retinal Lesions - Butz and van Ooyen 2013
    doi: 10.1371/journal.pcbi.1003259 downloadable here or see GoogleScholar.
    This paper is nicely summarised in a Science Daily article under the heading “Activity regulates synapse formation”: “...results show that the formation of new synapses is driven by the tendency of neurons to maintain a 'pre-set' electrical activity level. If the average electric activity falls below a certain threshold, the neurons begin to actively build new contact points. These are the basis for new synapses that deliver additional input - the neuron firing rate increases. This also works the other way round: as soon as the activity level exceeds an upper limit, the number of synaptic connections is reduced to prevent any overexcitation - the neuron firing rate falls. Similar forms of homeostasis frequently occur in nature, for example in the regulation of body temperature and blood sugar levels.”
31. ^ The Molecular and Systems Biology of Memory - Kandel, Dudai and Mayford 2014
    doi: 10.1016/j.cell.2014.03.001 downloadable here or see GoogleScholar.
    Page 164, part 1, end of first paragraph: “...the cellular connectionist approach, which derived from Cajal’s idea that memory is stored as an anatomical change in the strength of synaptic connections (1894)... (In 1948 Konorski renamed Cajal’s idea synaptic plasticity [the ability of neurons to modulate the strength of their synapses as a result of use].)”

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