Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors

There is a consensus that NMDA receptors (NMDARs) detect coincident pre- and postsynaptic activity during induction of long-term potentiation (LTP), but their role in timing-dependent long-term depression (tLTD) is unclear. We examine tLTD in neocortical layer 5 (L5) pyramidal pairs and find that tLTD is expressed presynaptically, implying retrograde signaling. CB1 agonists produce depression that mimics and occludes tLTD. This agonist-induced LTD requires presynaptic activity and NMDAR activation, but not postsynaptic Ca(2+) influx. Further experiments demonstrate the existence of presynaptic NMDARs that underlie the presynaptic activity dependence. Finally, manipulating cannabinoid breakdown alters the temporal window for tLTD. In conclusion, tLTD requires simultaneous activation of presynaptic NMDA and CB1 receptors. This novel form of coincidence detection may explain the temporal window of tLTD and may also impart synapse specificity to cannabinoid retrograde signaling.     

Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.At several excitatory and inhibitory synapses, neuronal activity can trigger enduring increases or decreases in neurotransmitter release, thereby producing long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength, respectively. In the last decade, many studies have revealed that these forms of plasticity are ubiquitously expressed in the mammalian brain, and accumulating evidence indicates that they may underlie behavioral adaptations occurring in vivo. These studies have also uncovered a wide range of induction mechanisms, which converge on the presynaptic terminal where an enduring modification in the neurotransmitter release process takes place. Interestingly, presynaptic forms of LTP/LTD can coexist with classical forms of postsynaptic plasticity. Such diversity expands the dynamic range and repertoire by which neurons modify their synaptic connections. This review discusses mechanistic aspects of presynaptic LTP and LTD at both excitatory and inhibitory synapses in the mammalian brain, with an emphasis on recent findings.     

A form of presynaptic coincidence detection

In this issue of Neuron, Sj?str?m et al. provide evidence for a novel presynaptic mechanism for coincidence detection in induction of timing-dependent LTD. In their scheme, simultaneous activation of presynaptic NMDA receptors and CB1 endocannabinoid receptors induces a long-lasting reduction in presynaptic transmitter release.     

Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity

Near coincidental pre- and postsynaptic action potentials induce associative long-term potentiation (LTP) or long-term depression (LTD), depending on the order of their timing. Here, we show that in visual cortex the rules of this spike-timing-dependent plasticity are not rigid, but shaped by neuromodulator receptors coupled to adenylyl cyclase (AC) and phospholipase C (PLC) signaling cascades. Activation of the AC and PLC cascades results in phosphorylation of postsynaptic glutamate receptors at sites that serve as specific "tags" for LTP and LTD. As a consequence, the outcome (i.e., whether LTP or LTD) of a given pattern of pre- and postsynaptic firing depends not only on the order of the timing, but also on the relative activation of neuromodulator receptors coupled to AC and PLC. These findings indicate that cholinergic and adrenergic neuromodulation associated with the behavioral state of the animal can control the gating and the polarity of cortical plasticity.     

Local learning rules: predicted influence of dendritic location on synaptic modification in spike-timing-dependent plasticity

Recent indirect experimental evidence suggests that synaptic plasticity changes along the dendrites of a neuron. Here we present a synaptic plasticity rule which is controlled by the properties of the pre- and postsynaptic signals. Using recorded membrane traces of back-propagating and dendritic spikes we demonstrate that LTP and LTD will depend specifically on the shape of the postsynaptic depolarization at a given dendritic site. We find that asymmetrical spike-timing-dependent plasticity (STDP) can be replaced by temporally symmetrical plasticity within physiologically relevant time windows if the postsynaptic depolarization rises shallow. Presynaptically the rule depends on the NMDA channel characteristic, and the model predicts that an increase in Mg²⁺ will attenuate the STDP curve without changing its shape. Furthermore, the model suggests that the profile of LTD should be governed by the postsynaptic signal while that of LTP mainly depends on the presynaptic signal shape.     

Depolarization gates spine calcium transients and spike-timing-dependent potentiation

Timing-dependent long-term potentiation (t-LTP) is induced when synaptic activity is immediately followed by one or more back-propagating action potentials (bAPs) in the postsynaptic cell. As a mechanistic explanation, it has been proposed that the bAP removes the Mg2+ block of synaptic NMDA receptors, allowing for rapid Ca2+ entry at the active synapse. Recent experimental studies suggest that this model is incomplete: NMDA receptor-based coincidence detection requires strong postsynaptic depolarization, usually provided by AMPA receptor currents. Apparently, the brief AMPA-EPSP does not only enable t-LTP, it is also responsible for the very narrow time window for t-LTP induction. The emerging consensus puts the spine in the center of coincidence detection, as active conductances on the spine together with the electrical resistance of the spine neck regulate the depolarization of the spine head and thus Ca2+ influx during pairing. A focus on postsynaptic voltage during synaptic activation not only encompasses spike-timing-dependent plasticity (STDP), but explains also the cooperativity and frequency-dependence of plasticity.     

Mechanisms and significance of spike-timing dependent plasticity

Hebb's original postulate left two important issues unaddressed: (i) what is the effective time window between pre- and postsynaptic activity that will result in potentiation? and (ii) what is the learning rule that underlies decreases in synaptic strength? While research over the past 2 decades has addressed these questions, several studies within the past 5 years have shown that synapses undergo long-term depression (LTD) or long-term potentiation (LTP) depending on the order of activity in the pre- and postsynaptic cells. This process has been referred to as spike-timing dependent plasticity (STDP). Here we discuss the experimental data on STDP, and develop models of the mechanisms that may underlie it. Specifically, we examine whether the standard model of LTP and LTD in which high and low levels of Ca(2+) produce LTP and LTD, respectively, can also account for STDP. We conclude that the standard model can account for a type of STDP in which, counterintuitively, LTD will be observed at some intervals in which the presynaptic cell fires before the postsynaptic cell. This form of STDP will also be sensitive to parameters such as the presence of an after depolarization following an action potential. Indeed, the sensitivity of this type of STDP to experimental parameters suggests that it may not play an important physiological role in vivo. We suggest that more robust forms of STDP, which do not exhibit LTD at pre-before-post intervals, are not accounted for by the standard model, and are likely to rely on a second coincidence detector in addition to the NMDA receptor.     

Glycine Induces Bidirectional Modifications in N-Methyl-d-aspartate Receptor-mediated Synaptic Responses in Hippocampal CA1 Neurons

Glycine can persistently potentiate or depress AMPA responses through differential actions on two binding sites: NMDA and glycine receptors. Whether glycine can induce long-lasting modifications in NMDA responses, however, remains unknown. Here, we report that glycine induces long-term potentiation (LTP) or long-term depression (LTD) of NMDA responses (Gly-LTP_NMDA or Gly-LTD_NMDA) in a dose-dependent manner in hippocampal CA1 neurons. These modifications of NMDA responses depend on NMDAR activation. In addition, the induction of Gly-LTP_NMDA requires binding of glycine with NMDARs, whereas Gly-LTD_NMDA requires that glycine bind with both sites on NMDARs and GlyRs. Moreover, activity-dependent exocytosis and endocytosis of postsynaptic NMDARs underlie glycine-induced bidirectional modification of NMDA excitatory postsynaptic currents. Thus, we conclude that glycine at different levels induces bidirectional plasticity of NMDA responses through differentially regulating NMDA receptor trafficking. Our present findings reveal important functions of the two glycine binding sites in gating the direction of synaptic plasticity in NMDA responses.     

Regulation of Long-Term Plasticity Induction by the Channel and C-Terminal Domains of GluN2 Subunits

Conventional long-term potentiation (LTP) and long-term depression (LTD) are induced by different patterns of synaptic stimulation, but both forms of synaptic modification require calcium influx through NMDA receptors (NMDARs). A prevailing model (the “calcium hypothesis”) suggests that high postsynaptic calcium elevation results in LTP, whereas moderate elevations give rise to LTD. Recently, additional evidence has come to suggest that differential activation of NMDAR subunits also factors in determining which type of plasticity is induced. While the growing amount of data suggest that activation of NMDARs containing specific GluN2 subunits plays an important role in the induction of plasticity, it remains less clear which subunit is tied to which form of plasticity. Additionally, it remains to be determined which properties of the subunits confer upon them the ability to differentially induce long-term plasticity. This review highlights recent studies suggesting differential roles for the subunits, as well as findings that begin to shed light on how two similar subunits may be linked to the induction of opposing forms of plasticity.     

Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner

Insulin and its receptor are both present in the central nervous system and are implicated in neuronal survival and hippocampal synaptic plasticity. Here we show that insulin activates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB), and results in an induction of long-term depression (LTD) in hippocampal CA1 neurones. Evaluation of the frequency-response curve of synaptic plasticity revealed that insulin induced LTD at 0.033 Hz and LTP at 10 Hz, whereas in the absence of insulin, 1 Hz induced LTD and 100 Hz induced LTP. LTD induction in the presence of insulin required low frequency synaptic stimulation (0.033 Hz) and blockade of GABAergic transmission. The LTD or LTP induced in the presence of insulin was N-methyl-d-aspartate (NMDA) receptor specific as it could be inhibited by alpha-amino-5-phosphonopentanoic acid (APV), a specific NMDA receptor antagonist. LTD induction was also facilitated by lowering the extracellular Mg(2+) concentration, indicating an involvement of NMDA receptors. Inhibition of PI3K signalling or discontinuing synaptic stimulation also prevented this LTD. These results show that insulin modulates activity-dependent synaptic plasticity, which requires activation of NMDA receptors and the PI3K pathway. The results obtained provide a mechanistic link between insulin and synaptic plasticity, and explain how insulin functions as a neuromodulator.     

The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses

In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr⁷⁵, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 μM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release.     

What mechanisms underlie involvement of different NMDA receptor subunits in the induction of hippocampal long-term potentiation and long-term depression?

There is a point of view that N-methyl-D-aspartate (NMDA) receptor subunit-specific signaling outcomes determine the direction of modifications of efficacy of synaptic transmission. Activation of NMDA receptors that contain the 2A subunit promotes LTP, while LTD requires activation of NMDA receptors containing 2B subunit. However, this hypothesis is inconsistent with some experimental data. For explanation of these data, we put forward an alternative hypothesis. According to this hypothesis, the activation of diverse subtypes of NMDA receptors can lead to ether LTP or LTD depending on the relation between posttetanic Ca2+ rise and increase in postsynaptic Ca2+ concentration produced by previous stimulation. Activation of NMDA receptors with 2B subunit can promote LTD of excitatory input to the pyramidal cell due to presence of these receptors on inhibitory interneurons, induction of the LTP in interneuron, and potentiation of inhibitory transmission between the interneuron and the target pyramidal cell.     

Synaptic mechanisms of associative memory in the amygdala

Do associative learning and synaptic long-term potentiation (LTP) depend on the same cellular mechanisms? Recent work in the amygdala reveals that LTP and Pavlovian fear conditioning induce similar changes in postsynaptic AMPA-type glutamate receptors and that occluding these changes by viral-mediated overexpression of a dominant-negative GluR1 construct attenuates both LTP and fear memory in rats. Novel forms of presynaptic plasticity in the lateral nucleus may also contribute to fear memory formation, bolstering the connection between synaptic plasticity mechanisms and associative learning and memory.     

钙依赖性突触的可塑性

突触前和突触后细胞内钙离子（[Ca^2 ]i)在短时程和长时程突触的可塑性中,发挥着重要的住处传递作用。兴奋后残留[Ca^2 ]i,可以激发短时程突触增强。突触前[Ca^2 ]i可以影响被抑制的突触前膜囊泡的更新,并准确编码突前和突触后信息,产生截然相反的长时程突触修（ＬＴＰ或ＬＴＤ）。     

Postsynaptic control of hippocampal long-term potentiation

Long-term potentiation (LTP) in the hippocampus has the property of cooperativity, i.e. greater potentiation is produced if a larger number of afferent fibres is tetanized. The possible involvement of postsynaptic mechanisms in this process was investigated in the CA1 area of the hippocampal slice preparation. Following blockade of postsynaptic inhibition by GABA antagonists, e.g. picrotoxin, the induction of LTP was greatly facilitated. In picrotoxin-treated slices, LTP was induced in a pathway stimulated by single volleys, if these occurred in conjunction with brief tetanic activation of other afferents. This interaction operated over a short period of time (less than 50 ms) and was also present if the inputs were separated in space (cooperativity between inputs to basal and apical dendrites). LTP could be induced by pairing single volley synaptic activation and intracellularly injected depolarizing current pulses, the timing requirements being similar to those observed in the extracellular "conjunction studies". Previous studies have suggested that glutamate receptor channels of the N-methyl-D-aspartate (NMDA) type are somehow involved in LTP induction. Evidence presented here shows that activation leading to LTP evokes a potential which is sensitive to the NMDA receptor blocker 2-amino-5-phosphonovalerate (APV), indicating passage of current through NMDA receptor channels. The results suggest that hippocampal LTP depends on simultaneous presynaptic transmitter release and postsynaptic depolarization in a manner analogous to the model proposed by HEBB (1949) for associative learning. Furthermore, it is proposed that the required pre- and postsynaptic interaction is handled by the NMDA receptor channel complex, which is known to have the required voltage and transmitter sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory

Cortical plasticity is thought to be important for the establishment, consolidation, and retrieval of permanent memory. Hippocampal long-term potentiation (LTP), a cellular mechanism of learning and memory, requires the activation of glutamate N-methyl-D-aspartate (NMDA) receptors. In particular, it has been suggested that NR2A-containing NMDA receptors are involved in LTP induction, whereas NR2B-containing receptors are involved in LTD induction in the hippocampus. However, LTP in the prefrontal cortex is less well characterized than in the hippocampus. Here we report that the activation of the NR2B and NR2A subunits of the NMDA receptor is critical for the induction of cingulate LTP, regardless of the induction protocol. Furthermore, pharmacological or genetic blockade of the NR2B subunit in the cingulate cortex impaired the formation of early contextual fear memory. Our results demonstrate that the NR2B subunit of the NMDA receptor in the prefrontal cortex is critically involved in both LTP and contextual memory.     

Synaptic neurotransmission depression in ventral tegmental dopamine neurons and cannabinoid-associated addictive learning

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.     

Postsynaptic complexin controls AMPA receptor exocytosis during LTP

Long-term potentiation (LTP) is a compelling synaptic correlate of learning and memory. LTP induction requires NMDA receptor (NMDAR) activation, which triggers SNARE-dependent exocytosis of AMPA receptors (AMPARs). However, the molecular mechanisms mediating AMPAR exocytosis induced by NMDAR activation remain largely unknown. Here, we show that complexin, a protein that regulates neurotransmitter release via binding to SNARE complexes, is essential for AMPAR exocytosis during LTP but not for the constitutive AMPAR exocytosis that maintains basal synaptic strength. The regulated postsynaptic AMPAR exocytosis during LTP requires binding of complexin to SNARE complexes. In hippocampal neurons, presynaptic complexin acts together with synaptotagmin-1 to mediate neurotransmitter release. However, postsynaptic synaptotagmin-1 is not required for complexin-dependent AMPAR exocytosis during LTP. These results suggest?a complexin-dependent molecular mechanism for regulating AMPAR delivery to synapses, a mechanism that is surprisingly similar to presynaptic exocytosis but controlled by regulators other than synaptotagmin-1.     

Ionotropic glutamate receptors

In the brain, most fast excitatory synaptic transmission is mediated through L-glutamate acting on postsynaptic ionotropic glutamate receptors. These receptors are of two kinds—the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate (non-NMDA) and theN-methyl-D-aspartate (NMDA) receptors, which are thought to be colocalized onto the same postsynaptic elements. This excitatory transmission can be modulated both upward and downward, long-term potentiation (LTP) and long-term depression (LTD), respectively. Whether the expression of LTP/LTD is pre-or postsynaptically located (or both) remains an enigma. This article will focus on what postsynaptic modifications of the ionotropic glutamate receptors may possibly underly long-term potentiation/depression. It will discuss the character of LTP/LTD with respect to the temporal characteristics and to the type of changes that appears in the non-NMDA and NMDA receptor-mediated synaptic currents, and what constraints these findings put on the possible expression mechanism(s) for LTP/LTD. It will be submitted that if a modification of the glutamate receptors does underly LTP/LTD, an increase/decrease in the number of functional receptors is the most plausible alternative. This change in receptor number will have to include a coordinated change of both the non-NMDA and the NMDA receptors.     

Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses

The physiological conditions under which adenosine A2A receptors modulate synaptic transmission are presently unclear. We show that A2A receptors are localized postsynaptically at synapses between mossy fibers and CA3 pyramidal cells and are essential for a form of long-term potentiation (LTP) of NMDA-EPSCs induced by short bursts of mossy fiber stimulation. This LTP spares AMPA-EPSCs and is likely induced and expressed postsynaptically. It depends on a postsynaptic Ca2+ rise, on G protein activation, and on Src kinase. In addition to A2A receptors, LTP of NMDA-EPSCs requires the activation of NMDA and mGluR5 receptors as potential sources of Ca2+ increase. LTP of NMDA-EPSCs displays a lower threshold for induction as compared with the conventional presynaptic mossy fiber LTP; however, the two forms of LTP can combine with stronger induction protocols. Thus, postsynaptic A2A receptors may potentially affect information processing in CA3 neuronal networks and memory performance.