Encyclopedia of Life Sciences || Synaptic Integration

Synaptic IntegrationSarah J Etherington, Murdoch University, Perth, Australia

Susan E Atkinson, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Greg J Stuart, Australian National University, Canberra, Australia

Stephen R Williams, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Based in part on the previous version of this Encyclopedia of Life Sciences(ELS) article, Synaptic Integration by Greg J Stuart andStephen R Williams.

Neurons in the brain receive thousands of synaptic inputs

from other neurons. Synaptic integration is the term used

to describe how neurons ‘add up’ these inputs before the

generation of a nerve impulse, or action potential. The

ability of synaptic inputs to effect neuronal output is

determined by a number of factors, including the size,

shape and relative timing of electrical potentials gener-

ated by synaptic inputs, the geometric structure of the

target neuron, the physical location of synaptic inputs

within that structure, as well as the expression of voltage-

gated channels in different regions of the neuronal

membrane. The process of synaptic integration is there-

fore modulated at multiple levels, contributing to the

diverse and complex computational powers of the func-

tioning brain.

Introduction

Neurons are powerful computational devices that processinformation received from thousands of other neuronsto form an output signal. This form of computation isdescribed as ‘synaptic integration’. The term ‘synaptic’refers to the specialised sites for communication betweenneurons, named synapses, where input signals to a neuronare generated. The neurons that generate input signals arecalled presynaptic neurons and the neuron that receivesthis input is called the postsynaptic neuron (Figure 1).Integration refers to the way the many inputs from

presynaptic neurons are summatedwithin the postsynapticneuron to generate an all or nothing output signal – theaction potential. See also: Neural Information Processing;SynapsesComplexity arises as presynaptic neurons form input

signals that either increase (excite) or decrease (inhibit) thelikelihood of action potential generation in the post-synaptic neuron. Furthermore, neurons typically have acomplex morphology, possessing intricate appendagestermed dendrites, on which the majority of synaptic con-tacts from presynaptic neurons are made (Figure 1). Oneconsequence of this is that the ability of synaptic inputs toinfluence the output of the postsynaptic neuronwill dependon their location within the dendritic tree relative to theaxon, the site where action potentials are generated.Moreover, synaptic inputs are usually quite brief in dur-ation, allowing only a short-timewindow for integration tooccur. The summation of synaptic inputs from differentpresynaptic neurons therefore depends on both their spa-tial distribution and their timing.Understanding how thesespatial and temporal factors contribute to the formation ofactionpotentials in the postsynaptic neuron is fundamentalto our attempts to understand how single neurons operate,and ultimately how the brain works. In this article weelaborate on these concepts and how they impact on theability of neurons to process the synaptic inputs theyreceive. See also: Neurons

Basic Neuronal Anatomy

Vertebrate neurons typically have a complicated morph-ology with numerous branching processes extending fromthe cell body, or soma (Figure 1). One of these processesforms the axon, the main output pathway of the neuron.The other processes are called the dendrites and theytypically form an intricate tree-like structure. Communi-cation between neurons takes place at specialised junctionscalled synapses. Dendrites can be thought of as the mainreceiving part of a neuron, and it is on to the dendrites thatthe vast majority of synaptic inputs to a neuron are made.Most of a neuron is in fact made up of its dendrites, which

Introductory article

Article Contents

. Introduction

. Basic Neuronal Anatomy

. Excitatory and Inhibitory Postsynaptic Potentials

. Factors Influencing Synaptic Integration

. Decision-making in the Axon

. Summary

Online posting date: 19th May 2010

ELS subject area: Neuroscience

How to cite:Etherington, Sarah J; Atkinson, Susan E; Stuart, Greg J; and Williams,

Stephen R (May 2010) Synaptic Integration. In: Encyclopedia of LifeSciences (ELS). John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0000208.pub2

ENCYCLOPEDIA OF LIFE SCIENCES & 2010, John Wiley & Sons, Ltd. www.els.net 1

http://dx.doi.org/10.1038/npg.els.0000149



can extend more than 1mm from the cell body, greatlyincreasing the area available for the establishment of syn-aptic contacts.

Synapses can either be electrical or chemical dependingon how signals are transmitted from one cell to the next. Atthe electrical synapse, ionic current flows directly betweenadjacent cells via simple channels called gap junctions. Atthe chemical synapse, an action potential in the nerveterminal of the presynaptic neuron causes the rapid release(within less than a millisecond) of small packets of achemical neurotransmitter. The released neurotransmitterbinds to surface receptors on the postsynaptic neuronallowing ion channels to open and current to flow.See also:Chemical Synapses; Neurotransmitter Receptors in thePostsynaptic Neuron; Neurotransmitter Release fromPresynaptic Terminals; Neurotransmitters

Excitatory and Inhibitory PostsynapticPotentials

During quiescent periods, when neurons are not receivingsynaptic inputs, an unequal distribution of charged ionsacross the neuronal membrane gives rise to a ‘restingmembrane potential’, where the inside of the cell is nega-tively charged with respect to the outside (e.g. 260mV).When synapses are activated, charged ions either flow intoor out of the postsynaptic neuron, according to their elec-trochemical driving force. The movement of charged ions

through specific ion channels produces a change in themembrane potential of the postsynaptic neuron. Thischange in membrane potential is called a postsynapticpotential (PSP), and represents the basic input signal to aneuron. The basic output signal of a neuron is the actionpotential, which is generated only when a critical mem-brane potential is reached, termed ‘action potentialthreshold’ (typically around 250mV). Whether or not aneuron reaches this threshold is determined by the balanceof synaptic inputs, which shift the membrane potentialcloser to (excitatory inputs) or further from (inhibitoryinputs) action potential threshold. See also: Ion Channels;Membrane PotentialWhether the opening of ion channels leads to an exci-

tatory or inhibitory response depends on the direction andcharge of the ions that move through activated channels(Figure 2). Inward movement of positive ions (e.g. sodium)is excitatory, whereas inward movement of negative ions(e.g. chloride) is inhibitory. The main excitatory neuro-transmitter in the brain is the amino acid glutamate,whereas the amino acid g-aminobutyric acid, orGABA forshort, is the main inhibitory neurotransmitter. The reasonone amino acid can be excitatory and another inhibitorylies in the nature of the ligand-gated ion channels openedbydifferent neurotransmitters. Glutamate binds to receptorsthat form ion channels that are predominantly selectivefor permeation by sodium and potassium ions, whereasGABA binds to receptors that form ion channels that arerelatively selective for permeation by chloride ions. Thereversal potential defines the potential at which the net

Apical dendrites

Basal dendrites

Soma

Axon

Presynaptic neuron

Postsynaptic neuron

Synaptic inputs

Figure 1 Schematic representation of the basic structure and synaptic connectivity between a pre- and postsynaptic neuron.

Synaptic Integration

ENCYCLOPEDIA OF LIFE SCIENCES & 2010, John Wiley & Sons, Ltd. www.els.net2









movement of charged ions into and out of the channel iszero, and for glutamate-activated channels is approxi-mately 0mV,whereas that forGABA-activated channels itis typically approximately 270mV. It is worth notingthat as the cell membrane potential passes the reversalpotential for a particular channel, the direction of net ionflow through that channel reverses. For example, at amembrane potential of268mV, themain ion flow throughGABA-activated channels is an inwards movement ofnegatively charged chloride ions, hyperpolarising thecell. By contrast, at a resting membrane potential of272mV, there will be a net outwards flow of (mostlychloride) ions through GABA-activated channels,resulting in a depolarising synaptic potential. Thus thesame GABA-activated ion channel can produce eitherhyperpolarisation or depolarisation of the postsynapticcell, depending on the cell membrane potential. See also:g-Aminobutyric Acid (GABA) Receptors; GABA as aNeurotransmitter and Neurogenic Signal; Glutamate as aNeurotransmitter; Glutamate Receptors; Ligand-GatedIon Channels

The action of excitatory neurotransmitters such as glu-tamate is to shift the membrane potential closer to actionpotential threshold (a process called membrane depolar-isation). If the magnitude of depolarizstion produced byexcitatory postsynaptic potentials (EPSPs) is sufficient toreach action potential threshold, an action potential will begenerated. However, the inhibitory neurotransmitterGABA acts to shift themembrane potential in the negativedirection closer to its reversal potential of 270mV

(membrane hyperpolarisation). As this process moves themembrane potential to values more negative thanaction potential threshold, inhibitory postsynaptic poten-tials (IPSPs) reduce the likelihood of action potential ini-tiation. See also: Action Potential: Ionic Mechanisms; CellMembranes: Intracellular pH and ElectrochemicalPotentialNeurotransmitter receptors responsible for IPSPs and

EPSPs in the brain canbe separated into two types, referredto as ionotropic andmetabotropic receptors, depending onthe mechanism by which transmitter binding leads to theopening (or closing) of ion channels. The binding ofneurotransmitter to ionotropic receptors causes the open-ing of an ion channel pore within the receptor complexitself. In contrast, the binding of neurotransmitter tometabotropic receptors activates a biochemical cascadethat can lead to the opening (or closing) of ion channelselsewhere. Activation of ionotropic receptors usually gen-erates postsynaptic potentials that are relatively brief induration (milliseconds to tens of millliseconds), whereasactivation of metabotropic receptors tends to generatepostsynaptic potentials that are relatively long lasting(hundreds of milliseconds to seconds). Ionotropic recep-tors are therefore said to mediate ‘fast’ synaptic transmis-sion between neurons, whereas metabotropic receptorsgenerate ‘slow’ synaptic transmission. In this article wefocus only on synaptic potentials mediated by ionotropicreceptors. See also: G Protein-coupled Receptors; Ligand-Gated Ion Channels; Metabotropic Glutamate Receptors;Neurotransmitters; Receptor Transduction Mechanisms

Na+ Cl−

High K+ Low Na+

K+

EPSP IPSP

High K+ Low Na+

−60 mV

−50 mV

−60 mV

−50 mVThreshold for AP firing

Resting membrane potential

+

Low K+

High Na+Low K+

High Na+

+

− − − − − −

+

Threshold for AP firing

Resting membrane potential

+ + +K+

Figure 2 Charge transfer across the neuronal membrane (bottom panels) and resulting change in neuronal membrane potential (top panels) during

generation of excitatory (EPSP) and inhibitory (IPSP) postsynaptic potentials.



http://dx.doi.org/10.1002/9780470015902.a0005907


















Factors Influencing SynapticIntegration

An individual neuron receives hundreds of synaptic inputs,both inhibitory and excitatory, and the process by whichthese inputs are combined to control neuronal output istermed synaptic integration. The main output signal of aneuron is the action potential, thus the impact of a givensynaptic potential on neuronal output depends on how italters themembrane potential at the site of action potentialgeneration (usually the axon initial segment). The initialamplitude of the synaptic potential and the efficacy withwhich it is conveyed to the site of action potential gener-ation can be influenced by a number of factors. Theseinclude the timing and location of coincident synapticinputs, the location of a given synapse within the dendritictree and the distribution and activation of voltage-gatedion channels (which open or close depending on the localelectrical environment) within the neuronal membrane.

Temporal summation and the time course ofsynaptic responses

In most neurons, EPSPs and IPSPs cause only a small (lessthan 1mV) change in membrane potential. Hence, a largenumber of EPSPs need to summate or ‘add up’ beforethreshold is reached and an action potential is generated(Figure 3). Furthermore, as aforementioned, neurotrans-mitters such as glutamate and GABA typically cause a

change in membrane potential that is quite brief (usuallyapproximately 10ms in duration), with a fast rising phasefollowed by a slower decay. The ability of EPSPs to sum-mate is therefore dependent on how quickly they are acti-vated in time. The summation of synaptic potentials overtime is called temporal summation.The number of EPSPs required to bring the postsynaptic

neuron to threshold for action potential generation willdepend on a number of important factors: (1) the ampli-tude of each individual EPSP, (2) the time course of indi-vidual EPSPs and (3) how close together in time EPSPs aregenerated. Clearly, if individual EPSPs are large in ampli-tude, then only one or a few EPSPs will be required todepolarise the postsynaptic neuron to threshold for actionpotential generation. Also, if EPSPs have a slow timecourse, individual EPSPswill be able to summate efficientlyover time, even if each presynaptic neuron produces EPSPsat very slow rates. The time course of a synaptic potential islargely determined by the properties of the postsynapticmembrane. Neuronal membranes provide resistance tovoltage changes (membrane resistance) and also havethe capacity to store charge (membrane capacitance). Theneuronal membrane resistance and capacitance, which areinfluenced by the membrane receptor density and surfacearea respectively, will determine how quickly the mem-brane potential changes when ion channels open and cur-rent flows across the membrane. These membraneproperties influence the time course of synaptic potentialsand therefore the window for temporal summation. Typi-cally, both EPSPs and IPSPs have a small amplitude and a

EPSP reversal(0 mV)

Action potentialthreshold (−50 mV)

Resting potential(−60 mV)

IPSP reversal(−70 mV)

EPSP EPSPsIPSP

Figure 3 Action potential generation during summation of excitatory postsynaptic potentials (EPSPs).



fast time course, meaning that temporal summation willoccur only when a large number of presynaptic neuronsrelease neurotransmitter at approximately the same time.

Importantly, EPSPs and IPSPs do not add up in a purelylinear manner, as the generation of one EPSP or IPSP canaffect the amplitude of subsequent EPSPs or IPSPs. Thishappens because of the effect of the first postsynapticpotential on the electrical driving force for ion flow duringthe second postsynaptic potential.When twoEPSPs or twoIPSPs sum, the second event is usually smaller owing to areduced driving force (a process termed nonlinear sum-mation, illustrated in Figure 4). The final number of EPSPsneeded to bring the neuron to threshold for actionpotentialgeneration will therefore depend on how effectively EPSPssummate, as well as the size, rate of occurrence and timecourse of other synaptic potentials that are generated in theneuron at the same time. See also: Action Potentials:Generation and Propagation

Spatial summation and the integration ofdistributed synaptic inputs

The synaptic inputs received by a neuron are distributedover a large area. The summation of EPSPs and IPSPsgenerated by synaptic inputs at different locations is calledspatial summation (summation in space). See also: Den-drites; Dendritic Spines

The extent of spatial summation of two synaptic inputsat different locations will depend on how effectively theyspread towards each other. The effectiveness with whichsynaptic potentials spread within a neuron depends largelyon the electrical properties of a neuron’smembrane and thegeometry of the dendritic tree. The membrane of a neuronis electrically ‘leaky’. That is, the electrical charge thatcauses the membrane potential to change during a post-synaptic potential leaks out, over time, through a group ofion channels termed ‘leak’ channels (these same channelshelp maintain the resting membrane potential). As a con-sequence, synaptic potentials attenuate as they spreadalong dendrites. For example, an EPSP might be 1mV inamplitude at the site where it is generated in the dendrites;however, by the time it has spread to the site of actionpotential generation in the axon, it may be one-tenth of itsoriginal amplitude. By analogy, a dendrite of a neuron issimilar to a water hose that has small holes punched alongits length. At each point along the hose some water willescape, so if 10L of water are pumped in at one end, only1L may be collected from the outlet. See also: PassivePropagation of Electrical SignalsIn dendrites the situation is more complicated, however,

as the neuronal membrane also acts as a capacitor, withopposite charges attracted to one another across the insu-lating cell membrane. This capacitance, combined with a‘leaky’ membrane, acts as an electrical filter, with the

Presynapticexcitatory neurons Presynaptic

inhibitoryinterneurons

Postsynaptic neuron

Postsynaptic response

Presynaptic input

Linear sum

Recorded response Linear sum

Recorded response

Figure 4 Nonlinear temporal summation of excitatory and inhibitory postsynaptic potentials, which occurs because the first of two overlapping synaptic

potentials alters the electrical gradient for ion movement during the second synaptic potential.










degree of filtering being greatest for the fastest rising anddecaying components of postsynaptic potentials. The netresult is that postsynaptic potentials are attenuated andslowed as they spread within the dendritic tree of neurons(Figure 5). The reduction in the amplitude of synapticpotentials is, however, partly balanced by their increasedduration. Functionally, this means that as synapticpotentials spread to the axon, they become smaller inamplitude, but longer in duration and so better suited forintegration over time (temporal summation).

The spatial segregation of synaptic inputs on to differentparts of the dendritic tree has advantages.One advantage isthe reduction of nonlinear summation of synaptic poten-tials. To illustrate this point, let us consider the situation ofa distributed excitatory synaptic input. In the brain onepresynaptic neuron typically makes several (usually fewerthan 10) separate synaptic connections with a postsynapticneuron. If all these connections were grouped tightlytogether on a small area of the postsynaptic neuron, forexample on one dendritic branch, the generation of anEPSP at one synaptic connection would decrease theamplitude of EPSPs generated by the other synaptic con-nections as a consequence of a reduction in electricaldriving force. If the same synaptic connections were dis-tributed over awide area, however, the local depolarisationproduced by each EPSP would have little effect on theelectrical driving force for EPSPs generated at the othersynaptic connections. The spatial distribution of synapticinputs, therefore, allows for the independent operation of

synapses when activated together. Indeed, the elaboratenature of the dendritic tree of neuronsmay have evolved inpart to fulfil this very function.

Critical role of synapse localisation

To trigger action potentials, synaptic potentials have tospread to the site in a neuron where action potentials areinitiated. This is typically in a region of the axon close tothe soma. How effectively synaptic events spread to thissite determines their ability to influence the output of theneuron. As a general rule, synaptic connections locatedcloser to the axon have the most influence on actionpotential generation. Indeed, many neurons have inhibi-tory synaptic connections placed directly on to the axon,precisely at the site of action potential generation. Theactivation of these inhibitory inputs exerts a powerfulnegative control over the generation of action potentials,in essence vetoing the influence of all excitatory synapticinput to the neuron. If the same group of inhibitory inputswere moved to a localised region of the dendritic tree, theywould have a less powerful effect on action potential gen-eration, but would be better placed to inhibit EPSPs gen-erated locally in that part of the dendritic tree. An evenmore specific way to control excitation occurs when theinhibitory inputs are located presynaptically, that is dir-ectly on the nerve terminals of excitatory presynapticneurons. In this unique case (called presynaptic inhibition)inhibitory input can modify the output of a single synapticconnection. See also: Heterosynaptic Modulation of Syn-aptic EfficacyThe location of synapses within the neuron, therefore,

has important functional consequences. In general, exci-tatory and inhibitory synaptic inputs located at sitesremote from the site of action potential generation have aless powerful control over neuronal output, unless mech-anisms are in place to compensate for the effect of theirremote location. For example, the number of channelsactivated during a synaptic potential could be larger atdendritic sites further away from the axon. This would actto compensate for the attenuation of more distal synapticpotentials as they spread to the axon. Alternatively, syn-aptic potentials generated at remote dendritic sites may beamplified by voltage-activated channels similar to the ionchannels involved in the generation and propagation ofaction potentials in the axon. This idea is discussed inmore detail in the next section. Neurons have thereforeevolvedmechanisms that could act tobalance for the effectsof synaptic location. See also: Voltage-gated PotassiumChannels

Voltage-gated ion channels in the dendritictree

Voltage-gated ion channels open or close in response tochanges in the potential difference across the cell mem-brane. When the channel pore is open, ions can flow fromone side of the membrane to the other and when closed ion

Synapse

EPSP at the synapse

EPSP at the soma

Figure 5 Attenuation of excitatory postsynaptic potentials (EPSPs) during

passive spread from their dendritic site of generation to the soma.







movement is prevented. Voltage-gated ion channels arepresent in dendritic membranes alongside ligand-gated ionchannels that respond to neurotransmitter binding.Duringsynaptic activity, the ion flow through ligand-gated chan-nels causes localised depolarisation or hyperpolarisation ofthe dendritic membrane, which can open or close localvoltage-gated channels. The subsequent change in ion flowthrough voltage-gated channels can alter the amplitude ortime course of the dendritic potential change, which in turninfluences the propagation of the synaptic event to thesoma. A variety of voltage-gated channels have beenidentified,with different ionic permeabilities and activationproperties (channel opening in response to different levelsof hyperpolarisation or depolarisation). This variety,coupled with differences in channel expression throughoutthe dendritic tree of neurons, means that voltage-gatedchannels can alter dendritic integration of synaptic inputsin a complex, cell type- and input-specificmanner (Figure 6).

When a region of the dendritic membrane contains ahigh density of voltage-gated sodium or calcium ionchannels that open in response to membrane depolar-isation, opening of these channels can become regenera-tive. That is, opening of some voltage-gated channels

allows an influx of positive ions that causes furtherdepolarisation and opening of more voltage-gated chan-nels. When this type of event occurs in dendrites theproduct of this regenerative depolarisation is called adendritic spike, as illustrated in Figure 7. Dendritic spikesare larger in amplitude than the sum of the EPSPs thatgenerated them, and so act to amplify dendritic synapticinputs. Importantly, dendritic spikes can actively propa-gate for some distance through the dendritic tree, furtherenhancing the impact of synaptic inputs on action potentialoutput.Another type of dendritic spike that has particular

implications for synaptic integration is the NMDA (N-methyl-D-aspartate) spike (Figure 8). NMDA receptorchannels differ from other ligand- and voltage-gatedchannels because they are jointly ligand- and voltage-gated. NMDA receptor-operated channels only conductcharge if depolarisation dislodges magnesium ions fromthe channel pore. This dual requirement for presynapticactivity as well as postsynaptic depolarisation means thatthe synchronous activation of multiple synaptic inputswithin a few tens of microns of one another is required togenerate an NMDA spike. Thus, NMDA spikes are

Low density ofVGCs

High density ofVGCs

Dendriticstimulatingelectrode

(1) Neuron without somato-dendriticVGC gradient

Somatic EPSP

Dendritic EPSP

Passive widening of EPSP during spread to thesoma is compensated for by the influence of voltage-gated ion channels.

EPSP half-width increases during passive spreadto the soma

Somatic EPSP

Dendritic EPSP

(2) Neuron with somato-dendritic VGCgradient (as illustrated)Dendritic

recordingelectrode

Somaticrecordingelectrode

Figure 6 Nonuniform dendritic distribution of voltage-gated ion channels (VGCs) modulates propagation of synaptic potentials towards the soma.



regenerative within the activated segment of the dendrite,but cannot spread actively outside of this region. If thedepolarisation generated by an NMDA spike spreadspassively to the soma it can cause a large somaticdepolarisation (of up to 10mV), therefore it has beenproposed that NMDA spikes allow a small region of den-dritic membrane to increase the saliency of synchronoussynaptic activity. See also: NMDA Receptors

As well as the generation of regenerative spikes withinthe dendrites themselves, dendritic integration of synapticinputs can be modulated by the spread of action potentialsfrom the soma back into the dendrite (Figure 9). In someneuronal types, this action potential ‘backpropagation’ ispassive and decays rapidly. In other neuronal types,regenerative activation of dendritic voltage-gated channelsenables active backpropagation of the action potentialthroughout the dendritic tree. Dendritic depolarisation bybackpropagating action potentials can temporarily alterthe properties of synaptic events, for example by tran-siently relieving the magnesium ion block of NMDAreceptors, acting as a trigger for the induction of synapticplasticity. As backpropagating action potentials usually

decay in amplitude as they propagate from the soma intothe dendritic tree, their influence on synaptic integrationwill vary between different locations in the dendritic tree.See also: Glutamate as a Neurotransmitter; SynapticPlasticity: Short Term

Decision-making in the Axon

The final site of synaptic integration in neurons is in theaxon, where action potentials are generated. The highdensity of voltage-gated ion channels in the axon meansthat excitation spreading from the dendrites to the axonleads to the generation of the action potential at thislocation, which then spreads back to the soma and den-drites, and forwards down the axon towards nerve term-inals. An action potential will be generated only if thebalance of all excitatory and inhibitory postsynapticpotentials at this site leads to a change in membranepotential that crosses the threshold for action potentialgeneration. The main role of the dendritic tree is thereforeto funnel synaptic inputs to the axon.Onemay askwhy not

Dendritic spike Dendritic spikethreshold

Action potentialthreshold

Axonal actionpotential

(2) The dendritic spikepropagates along thedendritic trunk with verylittle voltage attenuation.However, EPSPs doattenuate

(1) EPSPs summate tothreshold for re-generative voltage-gated Na+ and Ca2+

channel opening, adendritic spike is fired

(3) Axonal membranepotential reachesthreshold and anaction potential is initiated

(3) Axonal membrane potentialis subthreshold, no actionpotential output

Dendritic spikethreshold

Action potentialthreshold

(1) EPSPs summate, butdepolarisation insufficient totrigger regenerative openingof dendritic voltage-gatedNa+ channels

(2) EPSP amplitude attenuatesas EPSPs travel alongdendritic trunk

Synapticinput Synaptic input

Synaptic inputEPSPEPSP

Synaptic input

EPSP

EPSP

EPSP

1

2

3

Active Passive

Figure 7 Dendritic spikes, caused by regenerative opening of dendritic voltage-gated ion channels, can boost the somatic impact of synchronous synaptic

inputs.







Linear sum

Recorded response

Individual EPSPs

(a) Synchronous firing of synaptic inputs on different dendrite

(c) Cellular mechanism for NMDA spike

(b) Synchronous firing of two inputs on the same dendrite

(1) When a single input is active, only the NMDA receptors located in proximityto the synapse receive sufficient depolarisation and exposure to glutamate torelease the ‘channel Mg2+ block’and allow current to flow. More distant NMDAreceptors remain inactivate because of the Mg2+ block of the NMDA channel.

(2) When multiple inputs are synchronously and/or repetitively activated, the level ofpostsynaptic depolarisation generated by these synapses is sufficient to activateadditional NMDA receptors, provided they are close enough to an active synapse tobe exposed to glutamate. The depolarising current conducted by these receptorsgenerates an NMDA spike.

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Mg MgMg

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Action potential

Glutamate moleculeMg2+ ionMgNMDA receptor

NM

DAAMPA receptor

AM

PA

Distribution of glutamate Distribution ofdepolarisation

Figure 8 Mechanism of dendritic NMDA spikes. At the soma summation of synchronous synaptic potentials on different dendritic branches is usually close to linear (a); however, synchronous activation of

multiple synapses on the same dendritic branch can lead generation of a large depolarisation known as an NMDA spike (b). NMDA receptors are jointly ligand- and voltage-gated, meaning that NMDA-

receptor currents can be regenerative under certain conditions. This regenerative event is restricted to the activated region of the dendritic tree (c), but the associated depolarisation may spread to the soma.

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place all synaptic contacts directly at the site of actionpotential generation? Indeed, some neurons have a verysimple morphology, where synaptic contacts are all placedvery close to the site of action potential generation. Suchneurons subserve relatively simple relay tasks in the brain,where little synaptic integration is required. Neuronsinvolved in more complex information processing, how-ever, tend to have more elaborate dendritic trees. See also:Axons; Modulatory and Command Interneurons forBehaviour

The earlier discussion has outlined several reasons whyneurons have synaptic connections at dendritic locations,remote from the site of action potential generation. First,dendrites greatly expand the surface area of the neuron,allowing the establishment of a larger number of synapticcontacts. Second, the spatial distribution of synaptic con-tacts within the dendritic tree allows their independentoperation. Third, placement of excitatory and inhibitorysynaptic connections in specific patterns within the den-dritic tree allows local forms of dendritic integration to beperformed. The net result is a powerful computation unit(the single neuron), which processes thousands of synapticinputs dispersed in both time and space to produce anoutput signal that is conveyed to other neurons for furtherprocessing or as a final route to target organs and muscles.See also: Neural Networks and Behaviour

Axonal output: Not just all-or-none?

Synaptic integration is most commonly thought of as thetransformation of graded input signals (EPSPs and IPSPs)into an all-or-none output (the action potential), withinformation coded in the axon by the rate and pattern ofaction potential firing. What does this mean for subthres-hold electrical changes, such as EPSPs, that do not reachaction potential threshold? In terms of axonal output, is itas though they never happened? Not necessarily. In someneuronal types, axons convey two different types of infor-mation; the all-or-none action potential code (in whichthere are only two possible axonal states at any given time,firing or not firing) and an analogue (graded) signal due tothe passive spread of charge from the soma to the axon.During analogue axonal signalling, small, subthreshold

changes in the somatic resting membrane potential canspread passively for several hundredmicrometres along theaxon (Figure 10). The presence of voltage-gated channels inaxonal and terminal membranes means that this passivedepolarisation can affect neuronal output when anaction potential is subsequently generated, changing theshape of the axonal action potential or the availabilityof calcium channels in the nerve terminal, and thereforethe amount of neurotransmitter released at the synapse.For example, somatic depolarisation can inactivate

(1) Axon

(2) Soma

(3) Dendrite(control)

(4) Dendrite(TTX)

20 mV

0.5 ms

(4) Blockade of voltage-gatedsodium channels by TTXreduces the amplitude of thedendritic action potential,highlighting the importanceof active conductances inaction potentialbackpropagation

(3) Action potentialbackpropagates into the

apical dendrite, althoughthe amplitude is reduced

(2) Action potentialpropagates to soma(1) Action potential

generated in axoninitial segment

Figure 9 A backpropagating action potential occurs when depolarisation from an axonal action potential spreads back into the dendritic tree.







voltage-gated potassium channels in the axon, broadeningthe action potential waveform and enhancing transmitterrelease.

What are the implications of analogue axonal signallingfor synaptic integration? Importantly, analogue axonalsignalling means that small, subthreshold changes in theresting membrane potential of a cell can influence trans-mitter release in addition to that associatedwith the patternof action potential firing. As discussed earlier in the contextof dendritic events, the propagation of passive signals asthey travel along ‘leaky’ neuronal processes is stronglydetermined by the geometry of the neuronal process.Similarly, the effect of analogue signalling on transmitterrelease at nerve terminals depends heavily on the soma-terminal distance, and the size and branching pattern of theaxonal process. Non-uniform expression of voltage-gatedchannels in axonal processes provides an additionalmechanism for differentially affecting release at nerveterminals under different subthreshold conditions. Thus, asmall somatic depolarisation could selectively strengthentransmission in terminals close to the soma, whereas thestrength of distant synapses remains relatively constant.These mechanisms mean that subthreshold changes in the

resting membrane potentials of cells, such as occur inneuronal networks during different states of sleep andwakefulness, could produce very different neuronal outputsignals even in the face of identical patterns of synapticinput and dendritic integration.

Summary

Neurons in the brain receive thousands of synaptic inputsfrom other neurons. These inputs either increase ordecrease the likelihood that the membrane potential willreach the threshold for generation of an output signal – theaction potential. The ability of synaptic inputs to influenceaction potential initiation depends on their size, shape anddistance from the axon, as well as their relative timing andlocation. These factors influence the ability of synapticinputs to summate in time and space, and allow for non-linear interactions and the local processing of synapticinputs. This process, termed synaptic integration, is one ofthe features that give our brains the amazing computa-tional power that they have.

Apicaldendrite

Axoninitialsegment

Myelinatedaxon

SomaSoma

40 µm

480 µm

5 mV

200 ms

20 mV

200 µs

Digital signalling Analog signalling

20 mV

200 µs

5 mV

200 ms

An all-or-nothing response,where membrane potentialreaches a specific thresholdto elicit an action potential,which travels along the axonwith no attenuation. Theamplitude and time course ofeach AP remains constant

Subthreshold depolarisationcaused by incoming synapticactivity penetrates the axonand attenuates with distance. This affects the amplitudeand time course of subsequentaction potentials

Subthresholddepolarisation

Action potential

Figure 10 The passive spread of subthreshold somatic depolarisation into the axon, known as analogue axonal signalling, can alter the amplitude and time

course of the axonal action potential.



Further Reading

Bear MF, Connors BW and Paradiso MA (2006) Neuroscience:

Exploring the Brain, 3rd edn. Philadelphia: Lippincott.

Johnston D and Wu SM-S (1995) Foundations of Cellular

Neurophysiology. Cambridge, MA: MIT Press.

Kandel ER, Schwartz JH and Jessell TM (2000) Principles of

Neural Science, 4th edn. New York: Elsevier.

Shepherd GM (1997) The Synaptic Organization of the Brain, 4th

edn. Oxford: Oxford University Press.

Zigmond MJ, Bloom FE, Landis SC, Roberts JL and Squire LR

(1999) Fundamental Neuroscience. San Diego, CA: Academic

Press.



Documents

Encyclopedia of Life Sciences || Synaptic Integration