a central question in neuroscience is how memories are formed and stored in the brain .
studies in laboratory animals have demonstrated that learning occurs through activity - dependent synaptic strength modification .
given the sequential nature of many of our memories , it may come as no surprise that the temporal order of neuronal activity is a key determinant of synaptic plasticity .
the order of presynaptic and postsynaptic action potential firing within a millisecond time window leads to either strengthening or weakening of synapses [ 26 ] .
the involvement of postsynaptic ionotropic n - methyl - d - aspartate receptors ( nmdars ) in synaptic plasticity and spike - timing - dependent plasticity ( stdp ) has been well established .
coincident pre- and postsynaptic firing is detected by postsynaptic nmdars ( post - nmdars ) that take on the role of coincidence detectors due to their multiple requirements for activation , which include the binding of glutamate , a signal of presynaptic activity , and depolarisation , a signal of postsynaptic activity .
the depolarisation of the receptor is necessary in order to remove the magnesium ion ( mg ) blocking the channel pore at more hyperpolarised potentials , and is thought to be delivered by back propagation of somatic action potentials . activated postnmdars then permit the influx of calcium ( ca ) , which can set in motion intracellular ca - dependent mechanisms that lead to transient or lasting changes in synaptic strength via changes in postsynaptic -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor ( ampars ) expression and phosphorylation .  
temporal rules for spike - timing - dependent plasticity ( stdp ) are not the same for every synapse ; a diversity exists depending on brain area , neuron type , and location along dendrites [ 1114 ] . in juvenile rodent hippocampus , the window for synaptic modification
is restricted to about 40  ms [ 1417 ] and a sharp switch of the direction of synaptic change exists at the 0 millisecond timing interval .
in neocortical pyramidal neurons , the shape of the temporal stdp window depends on the location of synapses along the apical dendrite . in layer ( l ) 5 pyramidal neurons , proximal and distal synapses exhibit a progressive distance - dependent shift in the timing requirements for the induction of long - term potentiation ( ltp ) and long - term depression ( ltd ) [ 18 , 19 ] .
the mechanisms underlying these differences in timing rules rely on postsynaptic ca dynamics induced by back propagating action potentials : synapses at proximal dendritic locations experience sharper dendritic ca dynamics than distal synapses due to broadening of the action potential at distal dendrites [ 10 , 1821 ] . as a result of dendritic depolarisation ,
more ca enters the postsynaptic neuron through nmdars and voltage - gated ca channels ( vgccs ) [ 10 , 18 ] .   in recent years , it has become clear that other factors beyond ca influx through postnmdars control stdp and contribute to a diversity of timing rules at glutamatergic synapses [ 22 , 23 ] . in particular presynaptic ionotropic receptors , such as nmdars and nicotinic acetylcholine receptors ( nachrs ) ,
presynaptic ionotropic receptors located on presynaptic terminals are ideally suited to influence the efficacy of synaptic transmission by directly affecting neurotransmitter release [ 2426 ] .
short- and long - term activity - dependent modulation of the efficacy of synapses is crucial for regulating the flow of information throughout the nervous system and has been implicated in many neural processes , including learning .   for several of the presynaptically located ionotropic glutamate receptors  ampars , kainate receptors ( kars ) and nmdars  it has been reported that they not only regulate neurotransmitter release , but are also involved in short- and long - term modification of synapse strength .
for instance , hippocampal ca3 mossy fibre synapses onto pyramidal neurons show frequency facilitation on a seconds time - scale that involves activation of presynaptic kainate autoreceptors . on a minutes time scale , these presynaptic kainate receptors participate in the induction of ltp .
however , in these studies , the role of presynaptic kainate receptors in the temporal rules of spike - timing - dependent plasticity was not considered .
there is an abundance of anatomical and physiological evidence for the existence of presynaptic nmdars ( pre - nmdars ) in the mammalian neocortex , and many noncortical areas including the striatum [ 31 , 32 ] , hippocampus [ 3335 ] , and cerebellum [ 3638 ] .
physiological evidence for the existence of prenmdars came from the observation that activation of nmdars could lead to changes in transmitter release .
it is now clear that prenmdars are not only involved in modulating transmitter release , but also have a prominent role in synaptic plasticity [ 30 , 40 ] .
in fact , in several cortical areas , spike - timing - dependent synaptic depression ( tltd ) depends exclusively on prenmdars and not on postnmdars .  
the involvement of prenmdars in stdp was first shown at synapses between connected pairs of visual cortex l5 pyramidal neurons . at these synapses , a stimulation protocol where the postsynaptic neuron was brought to spike before the presynaptic neuron (  post - before - pre  ) induced tltd that was sensitive to nmda antagonists . both cv - analysis and
the reduction in short - term depression that accompanied tltd indicated a presynaptic expression mechanism .
the authors reasoned that since pre- and postsynaptic activity was required for tltd induction , but expression was presynaptic , a retrograde messenger would be required .
a prime candidate was endocannabinoids ( ecb ) , which are known retrograde messengers , capable of modulating presynaptic neurotransmitter release through cb1 receptors ( cb1r ) located on presynaptic terminals   ( wilson and nicoll ) .  
tltd was indeed found to be dependent on ecb signaling , since it was blocked by the cb1 receptor antagonist am251 .
ecb release by neurons is typically triggered by an increase in intracellular ca concentration   ( dimarzo [ 43 , 44 ] ) .   indeed , postsynaptic ca chelation with intracellular bapta blocked the induction of tltd .
presynaptic activity alone in presence of the cb1r agonist acea without postsynaptic spiking led to ecb - dependent ltd ( cltd ) , suggesting the requirement of postsynaptic activity for tltd serves only to trigger the release of ecbs .   surprisingly , cltd was still sensitive to bath applied nmdar antagonists , but since cltd was independent of postsynaptic activity , it is unlikely that the nmdars are located postsynaptically , because these would not be activated without postsynaptic depolarization .
also , nmdar stimulation led to an increase in mepsc frequency , suggesting prenmdars were located presynaptically .
based on these observations , the authors concluded that the most parsimonious explanation was that nmdars involved in tltd are located presynaptically .  
more reports on prenmdar - dependent tltd in visual cortex   and somatosensory cortex   soon followed .
there , tltd was also shown to be sensitive to bath applied nmdar antagonists , but to be independent of postnmdars , since tltd persisted when postnmdars were blocked by loading postsynaptic neurons with the use - dependent nmdar blocker mk-801 [ 45 , 46 ] or by hyperpolarizing the postsynaptic neuron at the time of the presynaptic spike .
the non - postsynaptic nmdars were assumed to be located presynaptically from the observed effect of nmdar stimulation on the frequency of spontaneous excitatory postsynaptic currents ( epscs )   and the amplitude of evoked ampar - mediated epscs , or by immunohistochemistry .   the definite proof that nmdars involved in tltd were indeed located on presynaptic neurons came from an elegant study in the rodent barrel cortex , where stdp plays a role in sensory whisker map formation . in l4 to l2/3 synapses , a pre - before - post induction protocol induced timing - dependent ltp ( tltp ) , and the reverse ( post - before - pre ) induced timing - dependent ltd .
rodriguez - moreno and paulsen   demonstrated that postsynaptic mk-801 blocked tltp , but not tltd whereas presynaptic mk-801 blocked tltd , but not tltp .
these results showed that tltp and tltd are dependent on different nmdars , namely postnmdars and prenmdars , respectively .  
it is important to note that most of the examples of tltd reported above are assumed to be mediated by nmdars located on , or at least close to , the synaptic terminals , because of the observed effects of nmdar stimulation on transmitter release [ 41 , 45 , 46 ] .
the reasoning behind this is that the increase in intracellular ca following nmdar activation is spatially limited to micro- or nanodomains , so in order for nmdar activation to affect the ca sensitive transmitter release processes , these receptors must lie close to the synaptic terminal .
the legitimacy of this assumption has been questioned , however , by the recent finding that subthreshold depolarization following activation of somatodendritic nmdars can affect axonal ca levels through recruitment of vgccs .
moreover , a follow - up study failed to detect changes in axonal ca   levels when directly applying nmda to axonal compartments of visual cortex l5 pyramidal neurons .
these new insights call for some caution when interpreting nmdar - mediated effects on synaptic transmission . therefore , although it remains difficult to imagine how such somatodendritic nmdars on presynaptic neurons would be recruited by tltd induction paradigms used in the above studies , their involvement can not be excluded .   to date , all forms of cortical prenmdar - dependent stdp reported in the literature involve tltd [ 23 , 41 , 45 , 46 , 51 ] , so it is unknown whether these presynaptic receptors can also mediate tltp . however , duguid and smart reported an intermediate form of ltp of inhibition in basket and stellate cell synapses onto purkinje cells in the cerebellum ; pairing presynaptic spiking with postsynaptic depolarisation resulted in a short period ( 2 - 3  min ) of depolarisation - induced suppression of inhibition ( dsi ) , which was followed by a prolonged period ( up to 15 minutes ) of  depolarisation - induced potentiation of inhibition  ( dpi ) .
secondly , dpi relies on prenmdars since it is abolished by ap-5 , but postsynaptic purkinje cells do not express nmdars at this age .
in addition , nmdar subunits colocalised with gad65/67 and synaptophysin , strongly suggesting that nmdars are located at the presynaptic terminal .
these results show that synaptic activity- and prenmdar - dependent plasticity can also be involved in potentiating synapses .  
having nmdars at presynaptic terminals involved in stdp raises questions on the nature of the underlying induction and expression mechanisms ; firstly , how do prenmdars become activated ? secondly , how does prenmdar activation lead to a lasting change in synaptic efficacy ? and thirdly , where is the change expressed ? in all the examples mentioned above , tltd was accompanied by changes in short - term plasticity .
this most likely reflects changes in release probability , pointing to a presynaptic site of expression .
it is not unlikely that it is the presynaptic influx of ca through activated prenmdars that triggers the lasting change in release probability . to date , the precise mechanisms by which such an nmdar - mediated ca influx can induce such changes have not been directly investigated , so the answer to the second question remains elusive .   how are prenmdars activated ? as mentioned before , nmdars require both depolarisation and binding of glutamate to become activated .
presynaptic action potential firing provides an obvious source of depolarisation to prenmdars , but the source of glutamate acting on these receptors is less obvious . a number of possible sources can be identified ( figure 1 ) .
firstly , as other presynaptic receptors , prenmdars can be activated by neurotransmitter released from the same nerve terminals on which the receptors themselves are located , thereby acting as autoreceptors [ 24 , 26 , 39 ] .
alternatively , glutamate may be released postsynaptically and act as a retrograde signal to activate prenmdars .
finally , glutamate can derive from sources outside the synapse , such as spill - over from synapses in the vicinity or glutamate release from nearby astrocytic processes .   at first glance , a role for prenmdars as auto - receptors on glutamatergic terminals may seem unlikely , because by the time glutamate released from the terminal on which the receptors are located has reached the prenmdars , the depolarisation causing its release may already have ended .
however , the prenmdars on which tltd of mouse barrel cortex l4 to l2/3 synapses depends were shown to contain nr2c / d subunits , which are known to be less voltage - sensitive
. therefore , they may be well - suited as prenmdars in this form of tltd , being able to activate when glutamate binds even without a strong depolarisation .
but tltd does not always rely on less voltage - sensitive nmdars ; prenmdar - dependent tltd at rat l5 to l5 visual cortex pyramidal neuron synapses and mouse l2/3 horizontal connections in barrel cortex relied on nr2b subunit - containing nmdars , which tend to have a higher voltage dependency . since nmdars are heteromeric structures , it remains possible that other nmdar subunits coassemble with nr2b to make the receptor less voltage sensitive .
if prenmdar - dependent tltd relies on nmdars with low voltage - sensitivity , glutamate binding with only a mild depolarisation could be sufficient for channel opening and prenmdars could function as auto - receptors after all .  
prenmdars could also be activated by postsynaptically released glutamate , which could ensure that nmdars are glutamate bound at the time of the presynaptic action potential .
this was shown to be the case in dpi of interneuron to purkinje cell synapses . since these synapses are gabaergic , prenmdars will not act as auto - receptors . by
pharmacologically blocking eaat - mediated glutamate reuptake , the hypothesis was tested that retrograde postsynaptic release of glutamate could activate prenmdars .
thus , the authors concluded that postsynaptically released glutamate may be responsible for activating prenmdars in this form of plasticity .
although dendritic glutamate release has been reported in cortical pyramidal neurons as well , it has thus far not been investigated whether prenmdar - dependent tltd also relies on retrograde glutamate signalling .  
spill - over from neighbouring glutamatergic synapses has been suggested before as a source of glutamate in other forms of prenmdar - dependent plasticity [ 56 , 57 ] .
however , in these studies neighbouring glutamatergic synapses were explicitly stimulated during plasticity induction . as a consequence , tltd at a specific synapse with prenmdars would then only occur if neighbouring glutamatergic synapses would be active .  
in recent years , it has become clear that glial cells are intimately involved in the active control of neuronal activity , synaptic transmission , and plasticity .
this has led to the concept of the tripartite synapse [ 5860 ] , where communication is not limited to the pre- and postsynaptic neuronal elements , but where there is also a bidirectional communication between neurons and the astrocytes ensheathing the synapse .
the potential importance of such astrocyte - neuron communication for synaptic plasticity was demonstrated recently in a study showing that astrocytic release of the neuromodulator d - serine was required for ltp at schaffer collateral synapses onto ca1 pyramidal neurons , although this is not without dispute .
it is not unthinkable that astrocytes fulfill a similar role in prenmdar - dependent tltd by releasing glutamate .
in fact , astrocytes have been reported to have the necessary intracellular machinery at their disposal for regulated exocytosis of glutamate   and such astrocyte - derived glutamate can readily activate prenmdars .
interestingly , prenmdars have been observed in extrasynaptic regions of presynaptic terminals closely apposed to glutamate - containing synaptic - like microvesicles in astrocytic processes .  
astrocytes express cb1 receptors which upon stimulation can trigger increases in intracellular ca levels leading to glutamate release [ 64 , 65 ] .
therefore , postsynaptically released ecbs may deliver signals of postsynaptic activity to nearby astrocytic processes .
indeed , postsynaptically released ecbs have been shown to potentiate synapses in hippocampus by inducing glutamate release from astrocytes which in turn activated presynaptic metabotropic glutamate receptors [ 65 , 66 ] . since prenmdar - dependent tltd at rat l5 to l5 visual cortex synapses , rat l4 to l2/3 barrel cortex synapses , and mouse l2/3 to l2/3 barrel cortex synapses , depended on ecb signalling as well , ecb signalling may be a general mechanism in prenmdar - dependent plasticity , serving to elicit glutamate release from astrocytes
.    the sequence of events that would have to take place in the case of ecb- and prenmdar - dependent tltd would be as follows ; during post - before - pre activity the postsynaptic neuron spikes first , allowing an increase in postsynaptic intracellular ca levels , which induces postsynaptic ecb release . activation of astrocytic ecb receptors induces increases in intracellular ca levels of the astrocyte which leads to the release of glutamate that binds to prenmdars .
the depolarisation associated with following presynaptic action potentials then activates prenmdars and the subsequent influx of ca triggers some as yet unknown intracellular mechanism that leads to a persistent reduction of glutamate release .
this scenario has one obvious difficulty ; the fact that prenmdar - dependent tltd can be induced using pre - before - post pairing intervals of only a few milliseconds puts severe time constraints on all the steps necessary within such a model .
this issue can potentially be resolved by considering the time - course of astrocytic ca signals , which typically take place on a seconds timescale [ 6770 ] .
therefore , ecb - mediated ca signals in astrocytes induced by the first pairings in the plasticity induction protocol may ensure glutamate levels are elevated during subsequent pairings .
definite proof of this sequence of events from postsynaptic ecb release to prenmdar activation by astrocytic glutamate release awaits experimental testing .
recently , banerjee et al .   reported that in mouse barrel cortex l4 to l2/3 synapses , prenmdar - dependent tltd was ecb independent .
these results raise the question of what other signalling mechanisms could be at play here .
one candidate molecule would be nitric oxide ( no ) , which has been shown to play a role in prenmdar - dependent cerebellar ltd .
in fact , no has been implicated in mediating the presynaptic component of tltp at the same barrel cortex l4 to l2/3 synapses in mice .
no derived from the postsynaptic neuron where it was released in response to postsynaptic depolarisation .
application of an no donor resulted in an increase in miniature epsc frequency , indicating a presynaptic action and suggesting that no is indeed employed as a retrograde messenger at these synapses . since no has also been shown capable of eliciting vesicular glutamate release by astrocytes , it is possible that prenmdar - dependent tltd in the mouse brain occurs through recruitment of astrocytes by no signalling .  
barrel cortex tltd of l4 to l2/3 synapses   and tltd of visual cortex l5 to l5 synapses   are two cases of prenmdar - dependent plasticity that share many similarities ; both require specifically timed pre- and postsynaptic activity , both are expressed presynaptically , and both require activation of both cb1rs and prenmdars . however , some differences seem to exist .
most importantly , as pointed out by duguid and sjstrm , in the presence of cb1 agonists , cltd could be induced in barrel cortex l4 to l2/3 synapses by trains of presynaptic stimulations delivered at either high ( 30  hz ) or low ( 0.1  hz ) frequencies .
this was not the case in l5 visual cortex neurons , where cltd was only induced at stimulation frequencies higher than 15  hz .
the latter finding is intriguing , because tltd at this synapse can be induced at low ( 0.1  hz ) post - before - pre pairing frequencies .
this suggests that at lower stimulation frequencies , some additional mechanism is needed besides ecb signalling .
possibly , as proposed by duguid and sjstrm , tltd at low stimulation frequencies relies on an additional retrograde signal from the postsynaptic cell .
as yet , the nature of this additional messenger can only be guessed at , but perhaps investigating the involvement of no would be a good place to start .
together , these results indicate that prenmdars often require the involvement of other signalling molecules or messenger systems to fulfill their role in plasticity .
it is important to know what precisely leads to prenmdar activation during stdp induction , as it has computational consequences for the role of prenmdar - dependent tltd in information processing .
prenmdars functioning as auto - receptors would mean they are detectors of specific intrinsic activities of the synapse .
however , if prenmdars are activated by glutamate from neighbouring cells , prenmdar - dependent tltd would be not only a reflection of coinciding pre- and postsynaptic activity , but also of coinciding activity of neurons and possibly astrocytes in the surrounding network .
acetylcholine ( ach ) is one of the major neurotransmitters in the brain involved in regulating neuronal network activity .
the effects of ach are mediated by two types of receptors ; the metabotropic muscarinic receptors ( machrs ) and the ionotropic nachrs .
nachrs are ion channels which open upon the binding of ach , permitting the influx of multiple ionic species , most notably sodium and calcium , resulting in membrane depolarisation .
brain nachrs are composed of multiple subunits , either heteromeric combinations of (210 ) and (24 ) subunits or homopentamers consisting of 7 subunits .
the precise subunit composition has a profound effect on the biophysical ( ca permeability , kinetics ) and pharmacological properties ( affinity , desensitization ) of the receptor [ 73 , 74 ] .
these receptors are present throughout the brain , and are often found at somatodendritic locations , where they influence the excitability of the cell .
however , just as nmdars , nachrs can also be found at presynaptic terminals in several brain regions , where they directly modulate excitatory glutamatergic transmission [ 7581 ] .
most of these presynaptic nachrs contain 7 subunits   and are thereby highly ca permeable , ideally suited to modulate the release of synaptic vesicles .
activation of presynaptic nachrs can induce synaptic plasticity . in the ventral tegmental area ( vta ) of the mesolimbic dopamine system , which is involved in reward processing , glutamatergic synapses on dopaminergic neurons
can undergo ltp when presynaptic activation is paired with postsynaptic activation , similar to cortical glutamatergic synapses [ 78 , 83 ] .
stimulation of presynaptic nachrs on these synapses by nicotine also induced ltp when this activation coincided with postsynaptic activity .
the amount of ltp that was induced correlated with the level of increase in excitatory synaptic transmission induced by nachr activation .
these effects on synaptic transmission were insensitive to ttx , indicating that the nachrs involved are located on , or close to the presynaptic terminals .
both changes in excitatory synaptic transmission and nicotine - induced ltp were mediated by 7 subunit - containing nachrs .
nicotine - induced ltp of glutamatergic inputs to da neurons depended on nmdar activation , which required postsynaptic depolarisation to remove the mg blockade .
it was recently shown that pre- as well as postsynaptic nachrs in the vta are involved in increasing glutamatergic synapse function , and initiating glutamatergic synaptic plasticity , which may be an important , early neuronal adaptation in nicotine reward and reinforcement .
nachrs can also modulate the rules for stdp , from locations further upstream than the presynaptic terminal . in l5
pyramidal neurons of mouse medial prefrontal cortex ( mpfc ) , pairing presynaptic and postsynaptic activity at 5  ms intervals induced a long - term strengthening of glutamatergic inputs .
when nachrs were stimulated with nicotine , tltp was eliminated and a depression of the excitatory inputs was observed .
this nicotinic modulation of plasticity was abolished by inhibitors of gaba type a ( gabaa ) receptors , indicating the effects of nicotine were due to its actions on presynaptic interneurons .
different types of gabaergic interneurons found in the pfc l5 express nachrs on their somas that activate these neurons when nicotine is present .
thereby , nachr stimulation enhanced gabaergic inputs to l5 pyramidal neuron dendrites , resulting in reduced ca entry during action potential back - propagation from the soma [ 22 , 85 ] . increasing dendritic action potential propagation by burst - like stimulation of the pyramidal neuron in the presence of nicotine could restore postsynaptic ca to levels comparable to those seen in the absence of nicotine , and restored stdp as well , indicating that strong postsynaptic stimulation could overcome the nicotinic modulation .
thus , activation of nachrs expressed by mpfc interneurons that inhibit dendrites can alter the rules for induction of stdp .   in mouse hippocampus
, timing - dependent plasticity can be modulated through a similar recruitment of inhibition by nachrs on presynaptic interneurons .
nachr activity could bidirectionally modulate plasticity , and the sign of synaptic change was critically dependent on the timing and localisation of nachr activation . in ca1
pyramidal neurons , pairing high - frequency stimulation ( hfs ) of schaffer collaterals with postsynaptic depolarisations resulted in short - term potentiation ( stp ) of these synapses .
with machrs blocked by atropine , a puff of ach in dendritic regions of the cell during plasticity induction boosted stp into ltp .
if , however , the ach puff was aimed at a neighbouring connected interneuron , the same protocol could no longer induce stp .
moreover , stimulating nachrs on nearby interneurons during a stronger plasticity induction protocol , capable of inducing ltp in control conditions , converted ltp into stp .
this demonstrates that timing and localization of nachr activity in the hippocampus can determine whether ltp will occur or not .
although the authors did not further investigate the mechanisms underlying the blockade of plasticity by interneuronal nachr activation , it is tempting to speculate that the resulting increase in inhibitory input reduces postsynaptic ca signals in ca1 pyramidal neurons in a similar manner as it does in l5 neurons of the mpfc .
plasticity induction by hfs does not involve back propagating action potentials , but increased inhibition may reduce the activation of postsynaptic voltage - dependent channels such as nmdars and vgccs that would otherwise be activated and promote synaptic potentiation .  
synaptic plasticity in the hippocampus has been associated with memory formation and synaptic plasticity in the pfc has been directly associated with attention and working memory .
activation of nachrs alters processes of synaptic plasticity in cortical and hippocampal neuronal networks . by altering ca dynamics during active dendritic signalling in apical dendrites
alternatively , nachrs may provide neuronal networks with the option to locally modulate synaptic plasticity , allowing a particular neuron or a particular synapse to respond differently than the average of the surrounding circuitry .   by
anatomical evidence shows that in rodent and human neocortex cholinergic nerve terminals establish classical synapses with closely apposed presynaptic and postsynaptic structures [ 89 , 90 ] , but direct physiological evidence for functional cholinergic synaptic transmission in the neocortex is lacking . in hippocampus ,
fast synaptic currents mediated by cholinergic transmission and 7 subunit - containing nachrs have been observed in interneurons , but not pyramidal neurons .
slow , tonic modes of ach release may act on neurons in a diffuse manner , although ach is rapidly broken down by the substantial levels of acetylcholinesterase in the neocortex . whether rapid phasic ach changes act directly or in a diffuse manner is not known .
recently it was shown that in the interpeduncular nucleus high - frequency ( 2050  hz ) stimulation of ach neurons eventually generates postsynaptic nachr - mediated responses via volume transmission [ 93 , 94 ] .
regardless , the findings above suggest that during fast or slow ach signalling the rules for stdp may be altered for shorter or longer time .
synapses can express multiple presynaptic ionotropic receptors that affect synaptic function and different types of ionotropic receptors can interact at the presynaptic level . for instance , activation of presynaptic ionotropic purinergic p2x receptors potentiates glutamate release due to the activation of 7-containing nachrs coexisting on rat neocortex glutamatergic terminals . considering the involvement of prenmdars and presynaptic nachrs in stdp , it would be interesting to examine whether these two species of receptors may also be found at the same synaptic terminals and if so , whether a similar interplay between nachrs and nmdars may occur . direct evidence for coexpression of presynaptic nachrs and nmdars
there , axonal 7 nachrs were found to modulate prenmdar expression , implicating presynaptic 7 nachr / nmdar interactions in synaptic development and plasticity .
firstly , in rat striatum , corticostriatal glutamate projections contain presynaptic 7 subunit - containing nachrs that upon stimulation elicit glutamate release . through microdialysis studies
it was shown that nmdars could enhance glutamate release as well in this area , which the authors suggested was due to activation of prenmdars on cortico - striatal nerve endings . secondly , in rat hippocampus , presynaptic 7 subunit - containing nachrs have been reported to exist on excitatory presynaptic terminals , where they increase spontaneous and evoked glutamate release .
these could well be the same synapses as where transmitter release - modulating prenmdars have been reported on a number of occasions [ 3335 ] . finally , in the neocortex where the prenmdar - dependent forms of tltd described above were observed , presynaptic nachrs
thus , several candidate synapses exist for co - expression of presynaptic nmdars and nachrs .  
co - expression of these presynaptic ionotropic receptors could have several distinct , though not mutually exclusive , consequences for stdp .
firstly , since presynaptic nachrs promote ltp , but prenmdars control ltd , there is the potential for an exciting competition to take place between potentiation and depression mechanisms at the presynaptic terminal .
it must be noted , however , that all examples given of presynaptic nachrs promoting ltp are non - cortical ( hippocampus , vta ) and ltd promoting prenmdars are cortical .
the most notable similarity between nachrs and nmdars is that they are both permeable to ca .
in fact , upon activation , 7 subunit - containing nachrs permit a ca influx that rivals that of nmdars .
the important difference with nmdars is , however , that nachrs do not have the voltage - dependent mg block .
so , activation of nachrs at resting membrane potentials directly leads to ca influx without the need for depolarisation . at depolarized potentials ( > 0  mv )
, however , an mg - dependent inward rectification takes place at nachrs that restricts the flow of current to very low levels [ 82 , 101 ] . in that sense , activity of nachrs and nmdars may complement each other , acting at more or less distinct ranges of membrane potentials .  
thirdly , a direct interaction by which the activity of one receptor affects the other may exist .
if nmdars and nachrs are expressed at the same synaptic terminal , local intracellular mg levels may lead to direct interaction between nachrs and nmdars ; activation of nmdars can result in a substantial increase in the intracellular concentrations of free mg .
this particularly affects 7 subunit - containing nachrs , which have stronger mg - dependent inward rectification than 2 subunit - containing nachrs .
therefore , at depolarized potentials , the increased mg levels following nmdar activation can act to inhibit nachrs and limit further ca influx through 7 subunit - containing nachrs .
this crosstalk may represent a means by which rapid rise in intracellular ca concentrations via activation of nmdars and nachrs can be tightly controlled , so that intracellular ca overloading is avoided
. such control over ca signals may be very important for plasticity processes and indeed , a coregulation of postsynaptic intracellular ca levels by nmdars and 7-containing nachrs to control synaptic plasticity has been proposed .  
the inverse , nachrs affecting the activity of nmdars , is also possible , albeit indirectly via intracellular signalling pathways .
it has been shown that 7-containing nachrs can activate calcineurin ( pp2b ) , a ca - sensitive enzyme , that when activated can lead to a reduction of the nmdar - mediated current decay time . by controlling the activity of pp2b
, nachrs can regulate nmdar transmission and synaptic plasticity [ 103 , 105 , 106 ] .
also , ca signals initiated by somatic or postsynaptic nachrs have been found to specifically reduce the amplitude of postnmdar - mediated currents through a ca - calmodulin - dependent process .
having two routes through different ionotropic receptors towards plasticity modulation could endow the synapse with the ability to have different learning rules for different modes of processing , for example , in the presence or absence of ach .
activation of these presynaptic receptors provides synapses with flexibility in the temporal rules for synaptic strengthening and weakening .
thereby , the presence or absence of specific neurotransmitters can create windows during which specific timing of neuronal activity will lead to synaptic changes or not .
for instance , hebbian plasticity is enhanced by behavioral relevance and attention , particularly in adults .
attentional gating of plasticity may be provided by neuromodulators such as ach released in cortex by basal forebrain inputs .
in addition , in barrel cortex , whisker map plasticity in s1 and other areas requires ach , and pairing of whisker stimuli with ach application drives receptive field plasticity .
this suggests that presynaptic ionotropic receptors may fundamentally gate or modify hebbian learning rules during appropriate behavioral contexts
. it will be interesting to learn from future research whether other types of presynaptic ionotropic receptors besides nmdars and nachrs are involved in controlling and shaping the rules for stdp .
 throughout life , activity - dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience . in line with predictions made by hebb 
 , synapse strength can be modified depending on the millisecond timing of action potential firing ( stdp ) . 
 the sign of synaptic plasticity depends on the spike order of presynaptic and postsynaptic neurons . 
 ionotropic neurotransmitter receptors , such as nmda receptors and nicotinic acetylcholine receptors , are intimately involved in setting the rules for synaptic strengthening and weakening . 
 in addition , timing rules for stdp within synapses are not fixed . 
 they can be altered by activation of ionotropic receptors located at , or close to , synapses . here 
 , we will highlight studies that uncovered how network actions control and modulate timing rules for stdp by activating presynaptic ionotropic receptors . furthermore 
 , we will discuss how interaction between different types of ionotropic receptors may create  timing  windows during which particular timing rules lead to synaptic changes . 
1. Introduction
2. Presynaptic NMDA Receptor-Dependent  Spike-Timing-Dependent Plasticity
3. Modulation of Timing-Dependent Plasticity by Presynaptic Nicotinic Acetylcholine  Receptors
4. Potential Interplay between Presynaptic   Ionotropic Receptors in STDP
5. Conclusion