Understanding presynaptic and postsynaptic inhibition

Understanding presynaptic and postsynaptic inhibition

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One way to classify neural inhibition is based on the inhibition being "presynaptic" or "postsynaptic".

As far as I understand, the two different types of inhibition refer to the following:

  • Presynaptic inhibition: A neuron N1 is inhibited "indirectly" insofar as the presynaptic excitatory neuron's action on it are dampened. This is typically achieved by neurotransmitter's impact on the presynaptic excitatory neuron which inhibit Ca2+ channels, and consequently prohibit vesicle release of neurotransmitter's into the synaptic cleft - hence the excitatory impact on neuron N1 is reduced.

  • Postsynaptic inhibition: A neurotransmitter acts directly on neuron N1's receptors, leading to hyperpolarization of the membrane potential and hence a reduced probability of firing.

My questions:

(1) When we speak of "inhibitory post-synaptic potentials" (IPSPs), is this hence always in the context of post-synaptic inhibition?

(2) I often read of "interneurons" (and it seems that this concept is used typically to refer to inhibitory neurons). Is inhibition by interneurons also always post-synaptic?

Post-synaptic vs pre-synaptic inhibition

Yes, inhibitory post-synaptic potentials (IPSPs) are always in the context of post-synaptic inhibition, because they are post-synaptic potentials. They occur because of inhibitory neurotransmitters (for example, GABA) are released and bind to post-synaptic receptors, particularly ligand-gated chloride channels. We often just call this "synaptic inhibition."

Pre-synaptic inhibition, on the other hand, would reduce the frequency/amplitude of excitatory post-synaptic potentials, by reducing neurotransmitter release at excitatory synapses (for example, glutamatergic synapses). You can also have pre-synaptic inhibition at an inhibitory synapse, where the pre-synaptic inhibition is actually disinhibitory from the perspective of the post-synaptic cell (inhibiting inhibition).

In summary: post-synaptic inhibition is reducing the rate or probability of action potentials; pre-synaptic inhibition is affecting the quantity or probability of vesicle release.

Interneurons vs inhibitory cells

Inhibitory interneurons are a major class of interneuron in the neocortex, but not all interneurons are inhibitory (layer 4 spiny stellate cells, for example, are excitatory interneurons). In addition, not all inhibitory cells are interneurons; some brain regions have inhibitory projection neurons, for example the cerebellum (Purkinje cells) or striatum (medium spiny neurons).

Inhibitory cells are those that release inhibitory neurotransmitters, so they are best thought of as involving post-synaptic inhibition. Chandalier cells in cortex are a bit of a special case, because they synapse onto axons and interfere with action potentials that way, but I would not lump them in with presynaptic inhibitory mechanisms.

Sources of pre-synaptic inhibition

In general (because there may be exceptions, and almost certainly are in invertebrates who have very "weird" nervous systems from my mammal-biased worldview), presynaptic inhibition arises from three places: autoreceptors (self receptors), retrograde signalling from post-synaptic cells, and neuromodulation. One could fill textbooks with information on all the mechanisms, but I'll give one example of each of the three types:


Glutamatergic synapses, for example, can have pre-synaptic inhibitory metabotropic glutamate receptors. These are G-protein coupled receptors, not ion channels, and they typically respond when a synapse is very active. They are effectively a brake on over-activity: if a cell is firing too much, the effect of its firing will be decreased by pre-synaptic inhibition mediated by these self-receptors. This principle is common for other neurotransmitters, too. (Wu & Saggau, 1997)

Presynaptic inhibition by post-synaptic cells

Although we think of neuronal signalling as one way, that's not entirely true. Post-synaptic cells have mechanisms to communicate with the pre-synaptic cell, and this can include inhibiting that cell.

Endocannabinoids are one mechanism: they are released by the post-synaptic cell and can reduce pre-synaptic release probability (Maejima et al 2001; Melis et al 2004). At an excitatory synapse, that makes them inhibitory; at an inhibitory synapse, they would be disinhibitory.

Pre-synaptic inhibition by neuromodulators

Pre-synaptic cells can also be affected by local concentrations of neuromodulators, like dopamine (Bamford et al 2004). Dopamine isn't necessarily released directly onto a cell but more into the surrounding area. Dopamine D2A receptors, for example, are found presynaptically at cortico-striatal synapses. Release of dopamine in the striatum reduces glutamate release at those synapses coming from cortex.

Bamford, N. S., Robinson, S., Palmiter, R. D., Joyce, J. A., Moore, C., & Meshul, C. K. (2004). Dopamine modulates release from corticostriatal terminals. Journal of Neuroscience, 24(43), 9541-9552.

Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A., & Kano, M. (2001). Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron, 31(3), 463-475.

Melis, M., Pistis, M., Perra, S., Muntoni, A. L., Pillolla, G., & Gessa, G. L. (2004). Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. Journal of Neuroscience, 24(1), 53-62.

Nadim, F., & Bucher, D. (2014). Neuromodulation of neurons and synapses. Current opinion in neurobiology, 29, 48-56.

Wu, L. G., & Saggau, P. (1997). Presynaptic inhibition of elicited neurotransmitter release. Trends in neurosciences, 20(5), 204-212.

Presynaptic inactivation of action potentials and postsynaptic inhibition of GABAA currents contribute to KA-induced disinhibition in CA1 pyramidal neurons

Kainate-type glutamate ionotropic receptors (KAR) mediate either depression or potentiation of inhibitory transmission. The mechanisms underlying the depressant effect of KAR agonists have been controversial. Under dual patch-clamp recording techniques in synaptically coupled pairs of CA1 interneurons and pyramidal neurons in hippocampal slices, micromolar concentrations of KAR agonists, kainic acid (KA, 10 microM) and ATPA (10 microM), induced inactivation of action potentials (APs) in 58 and 50% of presynaptic interneurons, respectively. Inactivation of interneuronal APs might have significantly contributed to KA-induced decreases in evoked inhibitory postsynaptic currents (eIPSCs) that are obtained by stimulating the stratum radiatum. With controlled interneuronal APs, KAR agonists induced a decrease in the potency (mean amplitude of successful events) and mean amplitude (including failures) of unitary inhibitory postsynaptic currents (uIPSCs) without significantly changing the success rate (P(s)) at perisomatic high-P(s) synapses. In contrast, KAR agonists induced a decrease in both the P(s) and potency of uIPSCs at dendritic high-P(s) synapses. KAR agonists induced an inhibition of GABA(A) currents by activating postsynaptic KARs in pyramidal neurons this was more prominent at dendrites than at soma. Both the exogenous GABA-induced current and the amplitude of miniature IPSCs (mIPSCs) were attenuated by KAR agonists. Thus the postsynaptic KAR-mediated inhibition of GABA(A) currents may contribute to the KAR agonist-induced decrease in the potency of uIPSCs and KA-induced disinhibition.

Author Summary

Synapses between neurons change during learning and memory formation, a process termed synaptic plasticity. Established models of plasticity rely on strengthening synapses of co-active neurons. In recurrent networks, mutually connected neurons tend to be co-active. The emerging positive feedback loop is believed to be counteracted by homeostatic mechanisms that aim to keep neural activity at a given set point. However, theoretical work indicates that experimentally observed forms of homeostasis are too slow to maintain stable network activity. In this article, we suggest that presynaptic inhibition can alleviate this problem. Presynaptic inhibition is an inhibitory mechanism that weakens synapses rather than suppressing neural activity. Using mathematical analyses and computer simulations, we show that presynaptic inhibition can compensate the strengthening of recurrent connections and thus stabilises neural networks subject to synaptic plasticity, even if homeostasis acts on biologically plausible timescales.

Citation: Naumann LB, Sprekeler H (2020) Presynaptic inhibition rapidly stabilises recurrent excitation in the face of plasticity. PLoS Comput Biol 16(8): e1008118.

Editor: Jonathan Rubin, University of Pittsburgh, UNITED STATES

Received: March 25, 2020 Accepted: July 1, 2020 Published: August 7, 2020

Copyright: © 2020 Naumann, Sprekeler. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Breathe, Walk and Chew: The Neural Challenge: Part II

Jean-Charles Viemari , . Laurent Vinay , in Progress in Brain Research , 2011


Synaptic inhibition mediated by GABA and glycine strongly modulates mammalian neuronal networks from the early life to adulthood. The postsynaptic action of these neurotransmitters on GABA A and glycine receptors depends on the intracellular concentration of chloride ions ([Cl − ]i) in the target cell. In adult healthy neurons, the activation of GABAA and glycine receptors results in an inward flux of Cl − and membrane potential hyperpolarization. Therefore, the inhibitory action of glycine and GABA consists in both shunting incoming excitatory currents and moving the membrane potential away from the action potential threshold. This “classical” hyperpolarizing inhibition is not observed in immature neurons inhibitory postsynaptic potentials (IPSPs) as well as glycine- and GABA-evoked potentials are instead depolarizing and often excitatory ( Gao and Ziskind-Conhaim, 1995 Takahashi, 1984 Wu et al., 1992 Ziskind-Conhaim, 1998 ), because of a high [Cl − ]i. The [Cl − ]i is regulated by transporters in the membrane ( Delpire and Mount, 2002 ). Chloride homeostasis and the regulation of those transporters appear as an important emerging mechanism, by which the strength, as well as the polarity, of postsynaptic inhibition can be controlled, even in adult tissue. This review will center on these issues.


Our results suggest the independent evolution of a novel and simple mechanism mediating an associative (Hebbian) LTP that involves postsynaptic induction and exclusively presynaptic expression – a form of LTP that has been highly anticipated following the discovery of NO as retrograde messenger. Presynaptic LTP is considered to provide a larger dynamical range of modulation relative to the postsynaptically expressed LTP (commonly mediated via NMDA dependent mechanism) 19 . This property is particularly characteristic of the octopus VL, where the probability of release (especially of fPSP1) is very low and it undergoes a huge presynaptic facilitation after LTP induction (e.g., 21 fold Fig. 2a,b). That is, our results suggest that in the octopus VL an efficient and powerful molecular mechanism has evolved to enable this unique form of LTP. This was achieved by adapting the NO system to mediate LTP expression and maintenance while in the currently known NO-dependent presynaptic LTP, NO is involved in LTP induction via the canonical NO dependent cGMP second messenger cascade 11,12,39 .

Taken together our results lead us to suggest a simple molecular-switch mechanism that comprehensively explains all the properties of the VL LTP and is summarized schematically in Fig. 4c. The NOS inhibitor (L-NNA) reversibly blocks the conversion of L-arginine into NO, thus reducing LTP expression. In the fast and irreversible inhibition mode, a regenerative synergy between reduction in NO concentration and the concomitant reduction in NO-dependent NOS-reactivation leads to a faster, complete and irreversible deactivation of NOS itself. The return of NOS to its inactivated state allows a new induction of LTP by HF stimulation. The spontaneous recovery of NOS activity following the drug washout is due to a residual unblocked NOS-activity which is enough for a regenerative, NO-dependent, full NOS reactivation. Note that the positive-feedback properties of this molecular cascade explain inhibition of expression alone or blocking both expression and maintenance. Yet, it is also possible that each inhibition mode is associated with different types of synapses as we found, for example, with respect to the dependence of LTP induction on the postsynaptic response 7 .

Although the exact biochemical mechanisms involved are still not entirely clear, our findings are reminiscent of the molecular-switches based on kinase autophosphorylation suggested for hippocampal LTP 40,41 . Still, our findings suggest a simpler dynamical molecular-switch that can flip rapidly between ON and OFF states due to a positive-feedback loop (resembling the kinetics of non-inactivated voltage-gated ion channels). As originally suggested 40 , such a molecular-switch, which is based on covalent modifications of existing molecules, can provide the means for consolidation of long-term memory irrespective of de novo protein synthesis, as indeed we found in the octopus VL. The VL LTP is important for long-term memory consolidation that occurs outside the VL 4 , and protein synthesis is important for long-term memory acquisition 42,43 . Consequently, the molecular memory switch in the octopus VL may persist only until completion of memory storage outside the VL. Because LTP expression and maintenance can in principle be switched OFF and ON again very rapidly, the molecular-switch may provide a convenient checkpoint for supervisory inputs to, for example, ‘veto’ LTP maintenance. Both the ability of IBMX to suppress transition to the long-term maintenance phase 37 and similar preliminary results with octopamine 44 support this idea.

For this molecular-switch to function in the framework of Hebbian induction it is reasonable to assume that NO does not activate NOS directly (or at least only at a very high concentrations), because otherwise LTP would also spread to neighboring synapses, obliterating the Hebbian property of synaptic specificity. This assumption is supported by finding that release of even relatively high NO concentrations from an NO donor (SNAP) did not induce LTP. Accordingly, and as previous results suggest 7 , LTP induction involves activity/Ca 2+ -dependent activation of NOS and possibly only the active form (NOS*) can be reactivated by NO (Fig. 4c). Such a molecular constellation will, on the one hand, lead to Ca 2+ -dependent NOS activation in the AMs, contributing to the postsynaptic component of a Hebbian induction mechanism. On the other hand, it ensures synaptic specificity, as only the presynaptic terminals in the immediate vicinity of the activated NOS in the postsynaptic cell will be facilitated retrogradely by NO 11,12 .

It still remains to determine the downstream biochemical cascade through which NO mediates its effects on transmitter release and on NOS reactivation. Currently, there are two main biochemical cascades known to mediate NO effects. The best documented involves NO-dependent activation of soluble guanylyl cyclase (sGC) in the cGMP/PKG cascade that functions at a very low NO concentration ranging from 100 pM up to 5 nM 36,39 . The second involves NO-induced covalent protein modification through a direct non-enzymatic s-nitrosylation of cysteine residues that requires a much higher NO concentration than the cGMP cascade 45,46 . We have found no indication for the involvement of the cGMP cascade in VL LTP. Moreover, NO donors and NO scavengers neither facilitated nor inhibited the fPSP, respectively. This suggests that these manipulations were ineffective in interfering with the physiological range of NO concentration in the VL, especially at the synaptic connections, where the effective concentration is likely the highest 12 . Thus, considering these negative results together with the amperometric measurements that indicate a μM range following LTP induction and during maintenance (Fig. 2g,h), the relatively high concentration of competitive NOS inhibitors (10 mM) and the intense NADPH-d activity (Fig. 1e-g), we raise the possibility that LTP expression in the VL is mediated by a non-enzymatic process and suggest s-nitrosylation as a possible candidate 46 . Auto s-nitrosylation of NOS has been reported, but in that case it inhibited NOS activity 47 . Conceivably, the higher concentration required for s-nitrosylation may suit better the locality of the retrograde message effect, ensuring synaptic specificity.

In conclusion, our results provide new physiological insights into the growing understanding that cephalopod evolution involved an outstanding flexibility in the selection of neuronal and morphological novelties. This evolutionary flexibility, at the neurophysiological level, has been demonstrated by the surprising finding of dichotomic differences in synaptic plasticity processes in the VLs of octopus and its phylogenetically close relative, the cuttlefish Sepia officinalis 5 . Especially interesting are preliminary results suggesting that NO and NOS activity are absent in the cuttlefish 48 . Recent genomic studies suggest that coleoid cephalopods are unique in adopting multiple regulatory mechanisms that allow more ‘modular’ developmental frameworks 49 . In addition, this group has a huge expansion of RNA re-editing sites that allow a unique post-translational modification of core gene products 50 . Such modular mechanisms may have also facilitated the selection of an alternative molecular mechanism for the mediation of LTP with specific properties suitable for achieving species-specific behavioral requirements.

Biology 222-Exam 3

-it had been known for many years that if you remove all extracellular calcium:

-amplitude and duration increased by prostigmine (an Acetylcholinesterase inhibitor)

-large trail to trail fluctuations

you can espitmae P(k=0) as number of failures/number of trials

-the presynaptic terminals at the frog NMJ are too small to penetrate with elecrodes, but other methods suggested that

-record response of presynaptic cell

-record response of postsynaptic cell

-graded with stimulus current

-micro-injection of the fast calcium chelator BAPTA (beginning after trial 1) greatly diminishes release (postsynaptic response became sub threshold)

-in presynaptic terminals (only voltage gated Ca current Ca current rises slowly, does not inactive)

-the NMJ shows (short term facilitation--paried pulse potentiation short term depression)

-katz showed that at the NMJ, both are due to changes in m

-vesicle release occurs spontaneously at a low rate. Presynaptic action potentials increase the rate of release 100,000 fold for a few milliseconds

-the rising phase of the calcium current is low, and release does not occur until several milliseconds have passed

-if the calcium channels are opened by stepping to the reversal potential: there is no presynaptic calcium current and no release

-synatpic delay results from the sluggish opening of calcium channels

-use physiological methods to determine which mutants act presynaptically

-identify the gene that is mutant

-the VSV-G protein is normally glycosylated in the Gogli by the enzyme GaINAc transferase

-use electron microscopy t identity sec mutant where vesicles stack up at the membrane, and os are potential fusion mutants

-vesicular neurotransmitter transporters

-identified 3 proteins that form a complex that tightly binds SNAP

-syntaxin (already found by Sudhof and Scheller as a plasma membrane protein)

-toxins known to eliminate neurotransmitter release cleave the three synaptic SNARe proteins so they cannot interact

-donor vesicles loaded with a fluorescent molecule, and a second molecule that quenches the fluorescence when bot hare very close together (very dim)

-test vesicles- nothing that absorbs light

-trace label: v test vesicle: synaptobrevin (VAMP)

-trace label: t test vesicle: syntaxin and SNAP-25

-at synapses
*one helix comes from the vesicle (synaptobrevins)
*three helices come from the plasma membrane (2 from SNAP-25, 1 from syntax's)

-in fruit fly, there appress to be only 1 gene

- in neurons in culture isolated from R223Q knock-in mice, the calcium dependence of release is altered

-they wanted to test whether the model of chemical synaptic function nabbing developed by Katz and collaborators for the from NMJ and validated by Kuffler and collaborators for the crayfish NMJ was general for excitatory synapses I the central nervous system

-repsonds normally in 0 external calcium

-electron microscope studies show no vesicles in presynaptic terminal

-an action potential in the MG produces a response in the Lg (bidirectional)

2. a presynaptic action potential cannot bring about postsynaptic inhibition

-apply drugs, to activate or block specific types of receptors

-vary the postsynaptic membrane potential of passing current

-current clamp conditions (fixed amplitude current steps chosen by the experimenter-measure potential change)

-the nicotinic receptors at the skeletal NMJ are cation channels with gNA=

*for a channel permeate to more than one ion, the reversal potential is a weighted average of the reversal potentials of all permeant ions

-For this Cell
*resting potential is -56mV
*the reversal potential (at Ecl) is -80mV, which is negative to action potential threshold in all cells, so this synapse is inhibitory

-the membrane potential a cell moves towards, when you open that type of channel at any potential other than the reversal potential (for this example, it is -20mV

-the membrane potential response is highly non-linear

-Ohms law defines the synaptic currst as

-switch on the voltage clamp. Amplifier Av measures the membrane potential

-you set the voltage to whatever you want (Command Potential)

-the voltage clamp current s equal I magnitude and opposite in sign to the current flowing through any ion channels that are open

-Ohms law defines the AChR current as (iAch=gAch(Vm-EAch)

-response to increasing conductance with a current clamp (as soon as channels open, the current flow depolarizes the cell, decreasing the driving force (Vm-EACh)

-Vm constant (because the voltage clamp forces it to be)

-the driving force determines the sign of the current (when the driving force is 0 (orange line) there is no current even though there are open channels

-if G synaptic is non-voltage dependent, plotting peak I as f(V) will be a straight line

-competitive: binds to same site as agonist

-the Hill coefficient is not the number of agonist binding sites (quantitative analysis of reaction mechanisms demonstrates that more binding sites often do lead to a steeper Hill coefficient

*Dentate granule neurons to CA3 pyramidal neurons (mossy fibers)

*CA3 pyramidal neurons to CA1 pyramidal neurons (Schaffer Collaterals

*granuale cells to purkinje neurons (> 100,000 to each target neuron)
*climbing fiber to purkinje neurons (only one presynaptic axon per target neuron)

*photoreceptor to bipolar and horizontal cells

-wait 1-2 days for high level receptor expression on surface

-demonstrate that injection polvA+ RNA from the rat brain results in responses. to glutamate in oocytes

-make a cDNA library from rat brain (about 850,000 cones)---divide into 18 pools of 40-50,000 clones

-make RNA in vitro from each pool and inject

-isolate related cDNAs by low stringency hybridization

-once the whole family had been identified
*use cloned sequence o make probes to identify sites of expression I the brainy northern blots and in situ hybridization
*characterize physiology and pharmacology Ain detail and compare with properties of native cells

-first crystal structures determined in 2009 for an AMPA receptor and more recently structures of all types have been characterized

-each subunit has 3 transmembrane helices (M1, M3, M4) and a region that enters and exits the membrane without crossing it (M2) (the Q/R/N site is at the inner-most point of M2)

-the majority of neurons have AMPA receptors with nearly linear I-Vs (and are calcium impermeable)
*these are the non-rectifying AMPA receptors

-produce prolonged response (>100ms) to brief (1ms) application of glutamate

-are inhibited by APV (AP5) and MK-801

-have a J-shaped I-V relation (outward rectification)

-ion substitution experiments showed that:
*the linear receptors are highly permeable to Na and K, but impermeable to Ca
*the inwardly rectifying receptors are highly permeable to Na and K, but even more permeable to Ca

-in the absence of glutamate, the gates on AMPA and CMDA receptors are closed. No current flows through these receptors

-when [glutamate] is low (A) only a few AMPA and NMDA receptors open their gates

-when [glutamates is high (B) many AMPA and NMDA receptors open their gates (large currents can flow through the AMPA-R, so the cell is greatly depolarized from resting potential)

-at this more positive potential
*becasue Omg is near 0 mV, Mg rarely tries to enter the cell via the NMDA-R, so the pore is not blocked
*Na or Ca can enter, K can K exit

-Mg tries to enter the cell via the NMDA-R, but gets tuck. No Na or Ca can enter, nor can K exit via NMDA-R

-or a negatively charged blocker could come from the outside

-pull outisde- out patches without or with polyamides in the intracellular solution (no inward rectification without polyamines

-strucutral information was obtained by cloning cDNAs then overexpressign in exogenous systems and carrying out electrophysiology and later, gyro-electron microscopy

-four types of subunits, but receptors are pentamers (5 subunits)
*in torpedo and in embryonic mammals, they are alph2 beta gamma delta
*in adults mammals, the gamma subunit is replaced by the very similar epsilon subunit

-all subunits have the same basic topology, and a shared evolutionary origin (the TM 2 domains line the pore- All are non-selective cation channels)

-there are lots of GABAa subunits
*19 total
*alph1-6, beta1-3, gamma1-3, delta, epsilon, pi, theta p1-3

-in adult brain Ecl is at or negative to resting potential, so it is inhibitory receptor of the human brain

- in the embryonic brain [Clin] is high, making Ecl close to 0mV, and GABA an excitatory transmitter

-the most common GABAaR isoforms contain two alpha subunits, two beta subunits, and one gamma or delta subunit

-most receptors containing a gamma subunit are located at synapses (have a relatively low affinity for GABA, activate quickly, desensitize extensively, and deactivate slowly

-receptors with delta subunit are located outside the synapse (have a relatively high affinity for GABA, activate slowly, desensitize minimally, and reactive rapidly)

-genetic variants of GABAaR subunits are inked to epilepsy, insomnia, anxiety, depression, schizophrenia, alcoholism, and autism

06 Jan Excitation and Inhibition

Most, if not all, neural information-processing functions involve the flow of action potential. Impulses in the nervous system are changes in the action potential or electrical charge of membranes. It is possible that, in addition to the membranes, the potential within the cytoplasm of the cell changes as a result of electrical flow in neurons. Potentials generally flow in one direction, from axons across synapses to dendrites, cell bodies, or other axons. Reverse transmission across synapses does not occur, although inhibitory responses can dull the effects of impulses.

The propagation of action potential can either be positive or negative. Positive waves or impulses are called excitatory and negative are called inhibitory (excitation and inhibition – collectively E/I). These action potentials vary widely in the amount of their positive or negative charges, and cumulative charges from multiple synapses will increase or decrease the action potential being propagated from cell to cell in the nervous system. Hyperpolarization can range from about -75 to -100 millivolts. Excitatory positive impulses depolarize the charge from -60 to +50 millivolts or more.

Understanding Context Cross-Reference
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Synapses and Neurotransmitters E/I Electric Potential Curve
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cognition cybernetics About Action Potential

Resting Potential

Neurons’ resting potential is about -70 millivolts they are said to be polarized with respect to external fluids. At any given time, most synapses are at resting potential. Inhibitory negative impulses increase or hyperpolarize the negative electromotive potential to -90 millivolts or further. Depolarization (excitation) reaches threshold value at around -40 millivolts. This curve illustration shows the attack curve of the excitatory impulse that occurs in the first millisecond of a typical excitatory impulse. This rise in the electrical potential is followed by a fall called its “decay.” Action potential decay at any point in a nerve fiber is usually as rapid as its firing. Impulses last around one millisecond.


When an impulse or spike arrives at a nerve ending, channels in the presynaptic membrane open. Where synaptic vesicles are in contact, neurotransmitter is released from the vesicles through the channel. Molecules of neurotransmitter chemical traverse the gap and bind with receptor molecules attached to the postsynaptic membrane. This causes channels in the target nerve’s fiber to open up, permitting the influx of positively charged sodium ions that are more concentrated outside the cell membrane than inside. The sodium residing in the cleft is the agent of excitation while other chemicals provide inhibition. The amount of neurotransmitter chemical released governs the aperture of the channels, thereby indirectly determining the intensity of the impulse transmitted.

Receptor channels are normally closed but they temporarily open when under the influence of neurotransmitters.The illustration at right shows a Closed Channel and an Open Channel. I like the way this video shows the process: Click here to see exocytosis. Here’s another that has nice subtitles.

The illustration below represents the shape of many impulses in the brain. Of course, human cognition involves the senses as well and possibly other nerve activities outside the brain, and those impulses may look very different as well. But this curve illustration is a good example to compare with computational models. The flow of electricity in a computer and its chips bears almost no resemblance to brain, neuron and synapse function or architecture. so as I seek to develop a model, I focus on the capabilities and the outcomes. But the mechanisms are important to the modeling assumptions I will be presenting in the next few posts.


Nerve impulses, triggered by changes in potential propagated through incoming synapses, accumulate at the place the axon leaves the soma. Channels in neuron membranes have gates at one or both ends that, when open, permit natural diffusion of chemicals through the membrane. Whether the voltage is positive or negative, this diffusion brings the voltage difference across the axon membrane closer to zero. Ahead of the affected region, channels in the membrane open and let sodium ions pour into the axon, creating a domino effect. Impulses travel from dendrites through the soma and down the axon to synapses. Stevens on the Flow of Sodium and Potassium Ions “The process is self-reinforcing: the flow of sodium ions through the membrane opens more channels and makes it easier for other ions to follow. The sodium ions that enter change the internal potential of the membrane from negative to positive. Soon after the sodium channels open, they close, and another group of channels open that let potassium ions flow out. This outflow restores the voltage inside the axon to its resting value of -70 millivolts” [Stevens, 1989, p. 7].

Ion Pumps

After the impulses have traveled down the axon to synapses, the resting potential of neurons and the proper disequilibrium of chemical molecular distribution is then restored by the action of ion pumps (see illustration). The restoration process affects potential latency and the permeability of membranes around the synaptic cleft. Thus, even when the level of excitation transmitted from one cell to the next is of limited intensity or duration, there is a time envelope during disequilibrium restoration in which membranes are more susceptible to electro-chemical influence. This is particularly useful in the muscular system because of our need to affect prolonged contractions for tasks like holding, carrying, and pushing. This will be discussed in more detail later.

In the context of cybernetics, the maintenance function provided by ion pumps presents interesting questions for modeling. For example, in an artificial neural network, how would the gradual return of a node (neuron) to resting potential be represented? Clearly, that process is opposed to the immediate spike and return with a short refraction period evidenced in many types of action potentials. Again, we will revisit this later.

The Entire Process

Mr. Beal’s Biology page has a great illustration of the chemical process cycle of an action potential:

The use of the term “undershoot” here and “overshoot” in other places should not be considered a contradiction. This beautiful illustration from Mr. Beals biology page helps in understanding the process. In upcoming posts – a little more detail on the curve itself.

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.

This pseudocolored image taken with a scanning electron microscope shows an axon terminal that was broken open to reveal synaptic vesicles (blue and orange) inside the neuron. (credit: modification of work by Tina Carvalho, NIH-NIGMS scale-bar data from Matt Russell)

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.

Communication at chemical synapses requires release of neurotransmitters. When the presynaptic membrane is depolarized, voltage-gated Ca 2+ channels open and allow Ca 2+ to enter the cell. The calcium entry causes synaptic vesicles to fuse with the membrane and release neurotransmitter molecules into the synaptic cleft. The neurotransmitter diffuses across the synaptic cleft and binds to ligand-gated ion channels in the postsynaptic membrane, resulting in a localized depolarization or hyperpolarization of the postsynaptic neuron.

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 Table. 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

In the context of biomolecular condensates, physical properties of the assembly of constituent macromolecules including viscosity, surface tension and porosity.

(Also known as surface tension). For separate liquid phases in contact with each other, the work required to increase the surface area of contact between the two phases. In the absence of external forces, interfacial/surface tension causes phase-separated liquids to form spherical droplets as spheres have minimal surface area for a given volume.

Interactions occurring between macromolecules with multiple sites of interaction, such that each molecule can interact with multiple binding partners.

Intrinsically disordered regions

Protein regions that do not adopt any stable ordered three-dimensional structure.

In the context of enzymology, the principle that the chemical reaction rate is proportional to the concentration of enzymes and substrates.

Ribulose bisphosphate carboxylase/oxygenase

(Rubisco). An enzyme acting in carbon fixation in photosynthetic organisms, catalysing the reaction between ribulose bisphosphate and atmospheric carbon dioxide.

Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase

(cGAS). An innate immune signalling enzyme that senses cytosolic DNA, a pathogen-associated molecular pattern, and produces cGAMP, which activates the stimulator of interferon genes (STING) protein to induce pro-inflammatory transcriptional responses.

Regulation of enzyme activity via binding by a second molecule at a site other than the enzyme’s active site, often by inducing a conformational change.

In simple molecular systems, a macromolecule that is required for condensate formation. The other, general group of condensate components are client molecules, which bind to and selectively partition into condensates without affecting condensate formation. In many natural condensates, this distinction is not absolute, and whereas some macromolecules act as pure scaffolds and some as pure clients, others can have varying impacts on the formation (threshold concentration) and composition of the compartment.

A parameter of the Michaelis–Menten model of enzyme kinetics, describing the concentration of a substrate molecule at which the rate of product formation reaches half of the maximum possible rate under a given set of conditions. If the rate of enzyme–substrate binding is rapid relative to catalysis, the KM value approximates the dissociation constant for the enzyme–substrate complex.

Nuclear condensates implicated in RNA base editing as well as transcriptional regulation. Paraspeckles are formed from the long non-coding RNA NEAT1 and the DBHS family of proteins (NONO, SFPQ and PSPC1).

A biochemical error-correction mechanism favouring reaction pathways that lead to correct over incorrect products, wherein an irreversible step that leads to exit of reaction intermediates from the pathway is more likely to occur for incorrect intermediates.

Cytoplasmic condensates found in yeast and humans that contains mRNA, RNA decapping and RNA degradation machinery. P bodies are thought to either store or degrade mRNA during stress.

A protein component of the RNA-induced silencing complex that binds several classes of small non-coding RNAs, which direct the complex to mRNA targets via sequence complementarity to downregulate expression through endonucleolytic mRNA cleavage or translational inhibition.

Transgenerational epigenetic inheritance

Biological processes that allow transmission of epigenetic regulatory molecules or modifications, such as RNAi factors or DNA methylation, from parent to offspring without altering DNA sequences.

Biomolecular condensates formed by liquid–liquid phase separation in Caenorhabditis elegans composed of RNA and proteins involved in the maintenance of germ cell fate via post-transcriptional regulation and small RNA biogenesis.

Biomolecular condensates in Caenorhabditis elegans containing the proteins ZNFX1 and WAGO4 required for transgenerational epigenetic inheritance of RNAi. Associates with both P granules and Mutator foci, forming a bridge between the two condensates.

A type of biomolecular condensate in Caenorhabditis elegans consisting of proteins encoded by mutator class genes, originally discovered in genetic screens for activation of transposons in the germline. Functions in siRNA amplification and RNA silencing.

Voltage-gated calcium channels

Membrane protein channels that allow ingress of calcium into the cell at presynaptic terminals of neurons when activated by membrane depolarization. Calcium activates exocytosis of neurotransmitter vesicles.

N-Methyl- d -aspartate (NMDA) receptor

A postsynaptic membrane protein channel activated by the excitatory neurotransmitter glutamate, allowing ingress of cations to depolarize the postsynaptic neuron.

Small protrusions on postsynaptic dendrites that are sites of excitatory signalling by glutamate neurotransmitter receptors.

A condensate specifically found during oocyte development that includes nuage, mitochondria and rough endoplasmic reticulum. Although the function is not fully understood, it is thought to preserve eggs in a dormant state prior to ovulation.

The use of highly focused laser beams to apply force to (‘trap’) very small objects.

A class of experimental techniques that introduce proteins or protein domain fusion constructs that have engineered small molecule-dependent activities into cells or in vitro biochemical reactions to achieve control over cellular or biochemical activities.

A class of experimental techniques using light-responsive proteins or engineered protein domain fusions to acutely modulate cellular or protein activities by illuminating cells or in vitro biochemical reactions.

The ratio of molecular concentration within a biomolecular condensate relative to the concentration in the surrounding solution.

For the binding of a molecule to some structure, a non-linear, saturable relationship between the molecular concentration and the fraction bound described by the rectangular hyperbola of the Michaelis–Menten model of enzyme kinetics.

Promyelocytic leukaemia nuclear bodies

Nuclear condensates formed by the promyelocytic leukaemia protein (PML). Fusion of PML to the retinoic acid receptor causes acute promyelocytic leukaemia. PML bodies are implicated in various processes, including transcription regulation, viral immunity, post-translational modification and apoptosis.

In cancer immunotherapy, T cells that express engineered T cell receptors (TCRs) where the native extracellular domains have been replaced by a heterologous binding domain targeted to a tumour-specific cell-surface protein in order to direct increased cytotoxic activity towards tumour cells.

A phenomenon in which a thermodynamically less stable state is maintained due to the high energy barrier, and thus long time period, required to move to the more stable state.

The use of an enzyme that has been expressed as two separate polypeptide chains and is only active when the fragments are brought together to reconstitute the full enzyme.