Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus

Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.     

Involvement of synaptic NR2B-containing NMDA receptors in long-term depression induction in the young rat visual cortex in vitro

Activation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in the induction of long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) in layer II/III pyramidal neurons of the young rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A- and NR2B-containing NMDARs in the induction of LTD in visual cortical slices from 12- to 15-day old rats. We found that LTD was readily induced in layer II/III pyramidal neurons of the rat visual cortex with 10-min 1-Hz stimulation paired with postsynaptic depolarization. D-APV, a selective NMDAR antagonist, blocked the induction of LTD. Moreover, the selective NR2B-containing NMDAR antagonists (Ro 25-6981 and ifenprodil) also prevented the induction of LTD. However, Zn2+, a voltage-independent NR2A-containing NMDAR antagonist, displayed no influence on the induction of LTD. These results suggest that the induction of LTD in layer II/III pyramidal neurons of the young rat visual cortex is NMDAR-dependent and requires NR2B-containing NMDARs, not NR2A-containing NMDARs.     

Phosphorylation of proteins involved in activity-dependent forms of synaptic plasticity is altered in hippocampal slices maintained in vitro

The acute hippocampal slice preparation has been widely used to study the cellular mechanisms underlying activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Although protein phosphorylation has a key role in LTP and LTD, little is known about how protein phosphorylation might be altered in hippocampal slices maintained in vitro. To begin to address this issue, we examined the effects of slicing and in vitro maintenance on phosphorylation of six proteins involved in LTP and/or LTD. We found that AMPA receptor (AMPAR) glutamate receptor 1 (GluR1) subunits are persistently dephosphorylated in slices maintained in vitro for up to 8 h. alpha calcium/calmodulin-dependent kinase II (alphaCamKII) was also strongly dephosphorylated during the first 3 h in vitro but thereafter recovered to near control levels. In contrast, phosphorylation of the extracellular signal-regulated kinase ERK2, the ERK kinase MEK, proline-rich tyrosine kinase 2 (Pyk2), and Src family kinases was significantly, but transiently, increased. Electrophysiological experiments revealed that the induction of LTD by low-frequency synaptic stimulation was sensitive to time in vitro. These findings indicate that phosphorylation of proteins involved in N-methyl-D-aspartate (NMDA) receptor-dependent forms of synaptic plasticity is altered in hippocampal slices and suggest that some of these changes can significantly influence the induction of LTD.     

Directional gating of synaptic plasticity by GPCRs and their distinct downstream signalling pathways

EMBO J 31 4, 805–816 (2012); published online December202011Synaptic plasticity, the activity-dependent modification of synaptic strength, plays a fundamental role in learning and memory as well as in developmental maturation of neuronal circuitry. However, how synaptic plasticity is induced and regulated remains poorly understood. In this issue of The EMBO Journal, Yang and colleagues present sets of exciting data, suggesting that G-protein-coupled receptors (GPCRs) selectively execute distinct signalling pathways to differentially regulate induction thresholds of hippocampal long-term potentiation (LTP) and long-term depression (LTD), thereby governing the direction of synaptic plasticity. These results shed significant light on our current understanding of how bidirectional synaptic plasticity is regulated.Synaptic plasticity has been demonstrated at synapses in various brain regions; the most well-characterized forms are LTP and LTD at hippocampal CA1 glutamatergic synapses (Collingridge et al, 2004). In experimental models, LTP and LTD can be, respectively, induced by high-frequency stimulation (HFS) and low-frequency stimulation (LFS) via activation of the N-methyl-D-aspartic acid (NMDA) subtype ionotropic glutamate receptor (NMDAR). However, how HFS and LFS activate NMDARs and thereby lead to synaptic plasticity remains poorly understood and highly controversial. It is even more unclear how the bidirectional synaptic plasticity is produced and regulated in response to physiological or pathological changes.Functional NMDARs consist primarily of two GluN1 subunits and two GluN2 subunits, with GluN2A and GluN2B subunits being the most common NMDAR subunits found in the cortical and hippocampal regions of the adult brain (Cull-Candy et al, 2001). GluN2A and GluN2B subunits may confer distinct gating and pharmacological properties to NMDARs and couple them to distinct intracellular signalling machineries (Cull-Candy et al, 2001). Moreover, the ratio of these two subpopulations of NMDARs at the glutamatergic synapse is dynamically regulated in an activity-dependent manner (Bellone and Nicoll, 2007; Cho et al, 2009; Xu et al, 2009). Although controversial, GluN2A- and GluN2B-containing NMDARs have been suggested to have differential roles in regulating the direction of synaptic plasticity (Collingridge et al, 2004; Morishita et al, 2007). Among the factors shown to regulate NMDAR function, Src family tyrosine kinases may be the best characterized, with both Src and Fyn able to upregulate NMDAR function, and thus LTP induction (Salter and Kalia, 2004). However, if these kinases modulate NMDAR function in a NMDAR subunit-specific manner remains unknown. To explore this concept, Yang et al (2012) investigated the potential subunit-specific regulation of NMDARs by Src and Fyn using whole-cell patch clamp recording of NMDAR-mediated currents from acutely dissociated CA1 hippocampal neurons or from rat hippocampal slices. They found that intracellular perfusion of recombinant Src or Fyn increased the NMDAR-mediated currents. By applying subunit-preferential antagonists of GluN2A- or GluN2B-containing NMDARs, or by using neurons obtained from GluN2A knockout mice, they discovered that Src and Fyn differentially enhanced currents gated through GluN2A- and GluN2B-containing NMDARs, respectively.Can physiological or pathological factors differentially activate Src or Fyn, thereby exerting subunit-specific regulation of NMDAR function? To answer this question, Yang et al focused their investigation on the role of GPCRs, specifically pituitary adenylate cyclase activating peptide receptor (PAC1R) and dopamine D1 receptor (D1R), both of which have recently been shown to potentiate NMDARs through Src family kinases (Macdonald et al, 2005; Hu et al, 2010). Indeed, they found that activation of PAC1R specifically increased GluN2A-NMDAR-mediated currents without affecting currents gated through GluN2B-NMDARs, and this potentiation was prevented by the Src-specific inhibitory peptide Src(40–58) (Salter and Kalia, 2004). To rule out the contribution of Fyn, the authors developed a novel-specific Fyn inhibitory peptide Fyn(39–57), and demonstrated that it had little effect on PAC1R potentiation. In contrast, activation of D1R potentiated GluN2B- (but not GluN2A-) NMDAR-mediated currents, and this potentiation was specifically eliminated by Fyn(39–57), but not by Src(40–58). The authors further demonstrated that stimulation of PAC1Rs resulted in a selective activation of Src kinase and consequent tyrosine phosphorylation of the GluN2A subunit, whereas activation of D1Rs led to a specific increase in Fyn-mediated tyrosine phosphorylation of the GluN2B subunit. To provide convincing evidence that these subunit-differential modulations are indeed the result of tyrosine phosphorylation of the respective NMDAR subunits, the authors then performed electrophysiological experiments using neurons from two knockin mouse lines GluN2A(Y1325F) and GluN2B(Y1472F), in which the tyrosine phosphorylation residues in native GluN2A and GluN2B subunits were, respectively, replaced with non-phosphorylatable phenylalanine residues. As expected, the authors found that PAC1R-mediated potentiation of NMDA currents was lost in neurons from GluN2A(Y1325F) mice (but maintained in neurons from GluN2B(Y1472F) mice), while D1R-mediated enhancement of NMDA currents was only observed in neurons from GluN2A(Y1325F) mice. Together, as illustrated in Figure 1, the authors have made a very convincing case that PAC1R and D1R, respectively, enhance function of GluN2A- and GluN2B-containing NMDARs by differentially activating Src- and Fyn-mediated phosphorylation of respective NMDAR subunits.Open in a separate windowFigure 1GPCRs regulate the direction of synaptic plasticity via activating distinct signalling pathways. Synaptic NMDA receptors, both GluN2A- and GluN2B-containing, play key roles in the induction of various forms of synaptic plasticity at the hippocampal CA1 glutamatergic synapse. Under the basal level of GluN2A and GluN2B ratio, stimulation with a train of pulses at frequencies from 1 to 100 Hz produces a frequency and plasticity (LTD–LTP) curve, with maximum LTD and LTP being, respectively, induced at 1 and 100 Hz. Activation of PAC1R with its agonist PACAP38 activates Src and thereby results in tyrosine phosphorylation and consequent functional upregulation of GluN2A-containing NMDARs, resulting in an increase in the ratio of functional GluN2A and GluN2B. The increased ratio in turn causes a left shift of frequency and plasticity curve, favouring LTP induction. In contrast, activation of D1R by the receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF81297","term_id":"1156277425","term_text":"SKF81297"}}SKF81297 triggers Fyn-specific tyrosine phosphorylation and functional upregulation of GluN2B, causing a reduction of GluN2A and GluN2B ratio. This decreased ratio results in a right shift of the curve, favouring LTD induction. The ability of GPCRs to differentially activate distinct downstream signalling pathways involved in synaptic plasticity suggests the potential roles of GPCRs in governing the direction of synaptic plasticity.Given the coupling of NMDARs to the induction of synaptic plasticity, it is then reasonable to ask if activation of the two GPCRs can selectively affect the induction of LTP or LTD at CA1 synapses. Yang and colleagues investigated the effects of pharmacological activation of PAC1R and D1R on the induction of LTP and LTD by recording the field excitatory postsynaptic potentials from hippocampal slices. Consistent with differential roles of NMDAR subunits in governing directions of synaptic plasticity, the authors observed that activation of PAC1Rs reduces the induction threshold of LTP, while stimulation of D1Rs favours LTD induction (Figure 1). Facilitation of LTP by PAC1R and LTD by D1R were, respectively, prevented in the brain slices obtained from GluN2A(Y1325F) and GluN2B(Y1472F) knockin mice, supporting the differential involvements of Src-mediated GluN2A phosphorylation and Fyn-mediated GluN2B phosphorylation.Taken together, the authors'' results have demonstrated that activation of PAC1R and D1R can control the direction of synaptic plasticity at the hippocampal CA1 synapse by differentially regulating NMDAR_EPSCs in a subunit-specific fashion (Figure 1). Specifically, PAC1R enhances the function of GluN2A-containing NMDARs by increasing Src phosphorylation of GluN2A subunit at Y1325, whereas D1R upregulates GluN2B-containing NMDARs through increased Fyn phosphorylation of GluN2B at Y1472. Moreover, by regulating the ratio of functional GluN2A- and GluN2B-containing NMDARs, PAC1R and D1R in turn modulate the direction of synaptic plasticity, favouring the production of LTP and LTD, respectively.While consistent with the recently proposed hypothesis that GluN2A and GluN2B may have preferential roles in the induction of hippocampal CA1 LTP and LTD (Collingridge et al, 2004; but see also Morishita et al, 2007), the current study further emphasizes the importance of GluN2A/GluN2B ratios in regulating LTP and LTD thresholds: increased ratio favours LTP, while reduced ratio promotes LTD. However, this seems to contradict some recent studies where the reduction and increase in the GluN2A/GluN2B ratio appeared to, respectively, favour LTP (Cho et al, 2009; Xu et al, 2009) and LTD (Xu et al, 2009). Therefore, the direction of plasticity change is likely modulated not only by the GluN2A/GluN2B ratio, but also by additional factors such as experimental conditions, developmental stages, and brain regions.Under many experimental conditions, LTP and LTD are usually induced by HFS and LFS stimulating protocols, respectively, but it remains essentially unknown how LTP and LTD are physiologically or pathologically generated in animals. To this end, the identification of different GPCRs as the endogenous upstream regulators of NMDA receptor subpopulations, and hence regulators of synaptic plasticity, is the major novelty of Yang and colleagues'' work. Future studies are needed to investigate if and how PAC1R and/or D1R are critically involved in the production of LTP or LTD in animals under physiological or pathological conditions. Given the fact that Src family kinases may be required for LTP induced by HFS in hippocampal slices (Salter and Kalia, 2004), an equally intriguing question would be whether these GPCRs are actually required for LTP/LTD induced by HFS/LFS experimental paradigms. In line with this conjecture, it would be interesting to determine if ligands for various GPCRs co-exist in the glutamatergic presynaptic terminals and, if so, can be differentially co-released with glutamate in a frequency-dependent manner, thereby contributing to either HFS-induced LTP or LFS-induced LTD.The findings by Yang and colleagues establish an exciting mechanistic model by which GPCRs can govern the direction of synaptic plasticity by determining the contributions of GluN2A- and GluN2B-NMDARs through differential tyrosine phosphorylation of respective NMDA receptor subtypes. Additional studies further validating this model under physiological and pathological conditions will greatly improve our understanding of the molecular mechanisms underlying synaptic plasticity and cognitive brain functions. In addition, NMDARs, depending on their subunit composition and/or subcellular localization, may also have complex roles in mediating neuronal survival and death (Lai et al, 2011). Considering that neurotoxicity produced by over-activation of NMDARs is widely accepted to be a common mechanism for neuronal loss in a number of acute brain injuries and chronic neurodegenerative diseases, Yang and colleagues'' finding of the differential regulation of NMDAR subunits by different GPCRs could have wider implications beyond synaptic plasticity.     

Long-term depression of kainate receptor-mediated synaptic transmission

Kainate receptors (KARs) have been shown to be involved in hippocampal mossy fiber long-term potentiation (LTP); however, it is not known if KARs are involved in the induction or expression of long-term depression (LTD), the other major form of long-term synaptic plasticity. Here we describe LTD of KAR-mediated synaptic transmission (EPSC(KA) LTD) in perirhinal cortex layer II/III neurons that is distinct from LTD of AMPAR-mediated transmission, which also coexists at the same synapses. Induction of EPSC(KA) LTD requires a rise in postsynaptic Ca(2+) but is independent of NMDARs or T-type voltage-gated Ca(2+) channels; however, it requires synaptic activation of inwardly rectifying KARs and release of Ca(2+) from stores. The synaptic KARs are regulated by tonically activated mGluR5, and expression of EPSC(KA) LTD occurs via a mechanism involving mGluR5, PKC, and PICK1 PDZ domain interactions. Thus, we describe the induction and expression mechanism of a form of synaptic plasticity, EPSC(KA) LTD.     

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.     

Effect of the Initial Synaptic State on the Probability to Induce Long-Term Potentiation and Depression

Long-term potentiation (LTP) and long-term depression (LTD) are the two major forms of long-lasting synaptic plasticity in the mammalian neurons, and are directly related to higher brain functions such as learning and memory. Experimentally, they are characterized by a change in the strength of a synaptic connection induced by repetitive and properly patterned stimulation protocols. Although many important details of the molecular events leading to LTP and LTD are known, experimenters often report problems in using standard induction protocols to obtain consistent results, especially for LTD in vivo. We hypothesize that a possible source of confusion in interpreting the results, from any given experiment on synaptic plasticity, can be the intrinsic limitation of the experimental techniques, which cannot take into account the actual state and peak conductance of the synapses before the conditioning protocol. In this article, we investigate the possibility that the same experimental protocol may result in different consequences (e.g., LTD instead of LTP), according to the initial conditions of the stimulated synapses, and can generate confusing results. Using biophysical models of synaptic plasticity and hippocampal CA1 pyramidal neurons, we study how, why, and to what extent the phenomena observed at the soma after induction of LTP/LTD reflects the actual (local) synaptic state. The model and the results suggest a physiologically plausible explanation for why LTD induction is experimentally difficult to obtain. They also suggest experimentally testable predictions on the stimulation protocols that may be more effective.     

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.     

Calcium-Dependent Desensitization of NMDA Receptors

Glutamate receptors play the key role in excitatory synaptic transmission in the central nervous system (CNS). N-methyl-D-aspartate-activated glutamate receptors (NMDARs) are ion channels permeable to sodium, potassium, and calcium ions that localize to the pre- and postsynaptic membranes, as well as extrasynaptic neuronal membrane. Calcium entry into dendritic spines is essential for long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. Both LTP and LTD represent morphological and functional changes occurring in the process of memory formation. NMDAR dysfunction is associated with epilepsy, schizophrenia, migraine, dementia, and neurodegenerative diseases. Prolonged activation of extrasynaptic NMDARs causes calcium overload and apoptosis of neurons. Here, we review recent findings on the molecular mechanisms of calcium-dependent NMDAR desensitization that ensures fast modulation of NMDAR conductance in the CNS and limits calcium entry into the cells under pathological conditions. We present the data on molecular determinants related to calcium-dependent NMDAR desensitization and functional interaction of NMDARs with other ion channels and transporters. We also describe association of NMDARs with lipid membrane microdomains.     

Computational investigation of the changing patterns of subtype specific NMDA receptor activation during physiological glutamatergic neurotransmission

NMDA receptors (NMDARs) are the major mediator of the postsynaptic response during synaptic neurotransmission. The diversity of roles for NMDARs in influencing synaptic plasticity and neuronal survival is often linked to selective activation of multiple NMDAR subtypes (NR1/NR2A-NMDARs, NR1/NR2B-NMDARs, and triheteromeric NR1/NR2A/NR2B-NMDARs). However, the lack of available pharmacological tools to block specific NMDAR populations leads to debates on the potential role for each NMDAR subtype in physiological signaling, including different models of synaptic plasticity. Here, we developed a computational model of glutamatergic signaling at a prototypical dendritic spine to examine the patterns of NMDAR subtype activation at temporal and spatial resolutions that are difficult to obtain experimentally. We demonstrate that NMDAR subtypes have different dynamic ranges of activation, with NR1/NR2A-NMDAR activation sensitive at univesicular glutamate release conditions, and NR2B containing NMDARs contributing at conditions of multivesicular release. We further show that NR1/NR2A-NMDAR signaling dominates in conditions simulating long-term depression (LTD), while the contribution of NR2B containing NMDAR significantly increases for stimulation frequencies that approximate long-term potentiation (LTP). Finally, we show that NR1/NR2A-NMDAR content significantly enhances response magnitude and fidelity at single synapses during chemical LTP and spike timed dependent plasticity induction, pointing out an important developmental switch in synaptic maturation. Together, our model suggests that NMDAR subtypes are differentially activated during different types of physiological glutamatergic signaling, enhancing the ability for individual spines to produce unique responses to these different inputs.     

Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory

Plasticity of the nervous system is dependent on mechanisms that regulate the strength of synaptic transmission. Excitatory synapses in the brain undergo long-term potentiation (LTP) and long-term depression (LTD), cellular models of learning and memory. Protein phosphorylation is required for the induction of many forms of synaptic plasticity, including LTP and LTD. However, the critical kinase substrates that mediate plasticity have not been identified. We previously reported that phosphorylation of the GluR1 subunit of AMPA receptors, which mediate rapid excitatory transmission in the brain, is modulated during LTP and LTD. To test if GluR1 phosphorylation is necessary for plasticity and learning and memory, we generated mice with knockin mutations in the GluR1 phosphorylation sites. The phosphomutant mice show deficits in LTD and LTP and have memory defects in spatial learning tasks. These results demonstrate that phosphorylation of GluR1 is critical for LTD and LTP expression and the retention of memories.     

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.     

Tag-Trigger-Consolidation: A Model of Early and Late Long-Term-Potentiation and Depression

Changes in synaptic efficacies need to be long-lasting in order to serve as a substrate for memory. Experimentally, synaptic plasticity exhibits phases covering the induction of long-term potentiation and depression (LTP/LTD) during the early phase of synaptic plasticity, the setting of synaptic tags, a trigger process for protein synthesis, and a slow transition leading to synaptic consolidation during the late phase of synaptic plasticity. We present a mathematical model that describes these different phases of synaptic plasticity. The model explains a large body of experimental data on synaptic tagging and capture, cross-tagging, and the late phases of LTP and LTD. Moreover, the model accounts for the dependence of LTP and LTD induction on voltage and presynaptic stimulation frequency. The stabilization of potentiated synapses during the transition from early to late LTP occurs by protein synthesis dynamics that are shared by groups of synapses. The functional consequence of this shared process is that previously stabilized patterns of strong or weak synapses onto the same postsynaptic neuron are well protected against later changes induced by LTP/LTD protocols at individual synapses.     

The NMDA Receptor NR1 Subunit is Critically Involved in the Regulation of NMDA Receptor Activity by C-terminal Src kinase (Csk)

Previous studies have shown that Csk plays critical roles in the regulation of neural development, differentiation and glutamate-mediated synaptic plasticity. It has been found that Csk associates with the NR2A and 2B subunits of N-methyl-D-aspartate receptors (NMDARs) in a Src activity-dependent manner and serves as an intrinsic mechanism to provide a “brake” on the induction of long-term synaptic potentiation (LTP) mediated by NMDARs. In contrast to the NR2A and 2B subunits, no apparent tyrosine phosphorylation is found in the NR1 subunit of NMDARs. Here, we report that Csk can also associate with the NR1 subunit in a Src activity-dependent manner. The truncation of the NR1 subunit C-tail which contains only one tyrosine (Y837) significantly reduced the Csk association with the NR1-1a/NR2A receptor complex. Furthermore, we found that either the truncation of NR2A C-tail at aa 857 or the mutation of Y837 in the NR1-1a subunit to phenylalanine blocked the inhibition of NR1-1a/NR2A receptors induced by intracellular application of Csk. Thus, both the NR1 and NR2 subunits are required for the regulation of NMDAR activity by Csk.     

Role of AMPA receptor trafficking in NMDA receptor-dependent synaptic plasticity in the rat lateral amygdala

Stimulated exocytosis and endocytosis of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors (AMPARs) have been proposed as primary mechanisms for the expression of hippocampal CA1 long-term potentiation (LTP) and long-term depression (LTD), respectively. LTP and LTD, the two most well characterized forms of synaptic plasticity, are thought to be important for learning and memory in behaving animals. Both LTP and LTD can also be induced in the lateral amygdala (LA), a critical structure involved in fear conditioning. However, the role of AMPAR trafficking in the expression of either LTP or LTD in this structure remains unclear. In this study, we show that NMDA receptor-dependent LTP and LTD can be reliably induced at the synapses of the auditory thalamic inputs to the LA in brain slices. The expression of LTP was prevented by post-synaptic blockade of vesicle-mediated exocytosis with application of a light chain of Clostridium tetanus neurotoxin and was associated with increased cell-surface AMPAR expression. In contrast, the expression of LTD was prevented by post-synaptic application of a glutamate receptor 2-derived interference peptide, which specifically blocks the stimulated clathrin-dependent endocytosis of AMPARs, and was correlated with a reduction in plasma membrane-surface expression of AMPARs. These results strongly suggest that regulated trafficking of post-synaptic AMPARs is also involved in the expression of LTP and LTD in the LA.     

LTP inhibits LTD in the hippocampus via regulation of GSK3beta

Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.     

Synaptic plasticity of NMDA receptors: mechanisms and functional implications

Beyond their well-established role as triggers for LTP and LTD of fast synaptic transmission mediated by AMPA receptors, an expanding body of evidence indicates that NMDA receptors (NMDARs) themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. NMDARs can significantly contribute to information transfer at synapses particularly during periods of repetitive activity. It is also increasingly recognized that NMDARs participate in dendritic synaptic integration and are critical for generating persistent activity of neural assemblies. Here we review recent advances on the mechanisms and functional consequences of NMDAR plasticity. Given the unique biophysical properties of NMDARs, synaptic plasticity of NMDAR-mediated transmission emerges as a particularly powerful mechanism for the fine tuning of information encoding and storage throughout the brain.     

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.     

Active dendrites,potassium channels and synaptic plasticity

The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons.