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1.  Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex 
Molecular Pain  2007;3:36.
Long-term potentiation (LTP) in the anterior cingulate cortex (ACC) is believed to be critical for higher brain functions including emotion, learning, memory and chronic pain. N-methyl-D-aspartate (NMDA) receptor-dependent LTP is well studied and is thought to be important for learning and memory in mammalian brains. As the downstream target of NMDA receptors, the extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinase (MAPK) cascade has been extensively studied for its involvement in synaptic plasticity, learning and memory in hippocampus. By contrast, the role of ERK in cingulate LTP has not been investigated. In this study, we examined whether LTP in ACC requires the activation of ERK. We found that P42/P44 MAPK inhibitors, PD98059 and U0126, suppressed the induction of cingulate LTP that was induced by presynaptic stimulation with postsynaptic depolarization (the pairing protocol). We also showed that cingulate LTP induced by two other different protocols was also blocked by PD98059. Moreover, we found that these two inhibitors had no effect on the maintenance of cingulate LTP. Inhibitors of c-Jun N-terminal kinase (JNK) and p38, other members of MAPK family, SP600125 and SB203850, suppressed the induction of cingulate LTP generated by the pairing protocol. Thus, our study suggests that the MAPK signaling pathway is involved in the induction of cingulate LTP and plays a critical role in physiological conditions.
doi:10.1186/1744-8069-3-36
PMCID: PMC2245920  PMID: 18053155
2.  AKAP Signaling Complexes in Regulation of Excitatory Synaptic Plasticity 
Plasticity at excitatory glutamatergic synapses in the central nervous system is believed to be critical for neuronal circuits to process and encode information allowing animals to perform complex behaviors such as learning and memory. In addition, alterations in synaptic plasticity are associated with human diseases including Alzheimer's, epilepsy, chronic pain, drug addiction, and schizophrenia. Long-term potentiation (LTP) and depression (LTD) in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease, respectively, the strength of synaptic transmission by postsynaptic AMPA-type glutamate receptors. Both LTP and LTD are induced by activation of NMDA-type glutamate receptors but differ in the level and duration of Ca2+ influx through the NMDA receptor and the subsequent engagement of downstream signaling by protein kinases including PKA, PKC, and CaMKII and phosphatases including PP1 and calcineurin-PP2B (CaN). This review addresses the important emerging roles of the A-kinase anchoring protein (AKAP) family of scaffold proteins in regulating localization of PKA and other kinases and phosphatases to postsynaptic multi-protein complexes that control NMDA and AMPA receptor function during LTP and LTD.
doi:10.1177/1073858410384740
PMCID: PMC3126619  PMID: 21498812
3.  Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state 
BMC Neuroscience  2005;6:48.
Background
The N-methyl-D-aspartate (NMDA)-type glutamate receptor expressed at excitatory glutamatergic synapses is required for learning and memory and is critical for normal brain function. At a cellular level, this receptor plays a pivotal role in triggering and controlling synaptic plasticity. While it has been long recognized that this receptor plays a regulatory role, it was considered by many to be itself immune to synaptic activity-induced plasticity. More recently, we and others have shown that NMDA receptor-mediated synaptic responses can be subject to activity-dependent depression.
Results
Here we show that depression of synaptic transmission mediated by NMDA receptors displays a state-dependence in its plasticity; NMDA receptors are resistant to activity-induced changes at silent and recently-silent synapses. Once synapses transition to the active state however, NMDA receptors become fully 'plastic'. This state-dependence is identical to that shown by the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor. Furthermore, the down-regulation of NMDAR-mediated responses during synaptic depression is prevented by disruption of dynamin-dependent endocytosis.
Conclusion
NMDA receptor-mediated synaptic responses are plastic in a state-dependent manner. Depending on the plasticity state in which a synapse currently resides, NMDA receptors will either be available or unavailable for down-regulation. The mechanism underlying the down-regulation of NMDA receptor-mediated synaptic responses is endocytosis of the NMDA receptor. Other potential mechanisms, such as receptor diffusion along the plane of the membrane, or changes in the activity of the channel are not supported. The mechanisms of AMPA receptor and NMDA receptor endocytosis appear to be tightly coupled, as both are either available or unavailable for endocytosis in the same synaptic states. Endocytosis of NMDA receptors would serve as a potent mechanism for metaplasticity. Such state-dependent regulation of NMDAR endocytosis will provide fundamental control over downstream NMDA receptor-dependent plasticity of neuronal circuitry.
doi:10.1186/1471-2202-6-48
PMCID: PMC1187896  PMID: 16042781
4.  Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex 
Molecular Pain  2009;5:46.
Cortical areas including the anterior cingulate cortex (ACC) are important for pain and pleasure. Recent studies using genetic and physiological approaches have demonstrated that the investigation of basic mechanism for long-term potentiation (LTP) in the ACC may reveal key cellular and molecular mechanisms for chronic pain in the cortex. Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits. However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated. Here, we report that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluA1 but not GluA2 contributes to LTP in the ACC using genetic manipulated mice lacking GluA1 or GluA2 gene. Furthermore, GluA1 knockout mice showed decreased extracellular signal-regulated kinase (ERK) phosphorylation in the ACC in inflammatory pain models in vivo. Our results demonstrate that AMPA receptor subunit GluA1 is a key mechanism for the expression of ACC LTP and inflammation-induced long-term plastic changes in the ACC.
doi:10.1186/1744-8069-5-46
PMCID: PMC2734546  PMID: 19664265
5.  Expression mechanisms underlying long-term potentiation: a postsynaptic view. 
This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particular N-methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.
doi:10.1098/rstb.2002.1228
PMCID: PMC1693172  PMID: 12740118
6.  Enhanced synaptic long-term potentiation in the anterior cingulate cortex of adult wild mice as compared with that in laboratory mice 
Molecular Brain  2009;2:11.
Activation of N-methyl D-aspartate (NMDA) receptor is important for learning, memory and persistent pain. Genetic enhancement of NMDA receptor function by overexpressing NR2B subunit significantly enhances hippocampal long-term potentiation (LTP), behavioral learning as well as persistent pain. Recent studies found that NMDA NR2B subunits can undergo long-term upregulation in the brain under certain conditions including peripheral injury and environmental enrichment. Considering the fact that laboratory grown animals live in an artificial comfort environment, we wondered if NMDA receptor functions and its related LTP would differ in animals living in a natural wild environment. In this report we performed whole-cell patch-clamp recordings from both laboratory wild-type mice and wild mice from a natural environment. We found that LTP was significantly enhanced in the anterior cingulate cortex (ACC) of the wild mice as compared with that of laboratory mice. In parallel, NMDA receptor NR2B/total NMDA receptor mediated EPSC ratio was significantly increased in slices of wild mice. Our findings provide the first evidence that NMDA NR2B receptors play an important role in experience-dependent synaptic potentiation within the ACC in wild mice as previously reported in laboratory mice.
doi:10.1186/1756-6606-2-11
PMCID: PMC2694782  PMID: 19445686
7.  Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats 
Neurobiology of Aging  2011;33(9):1938-1949.
Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-R) receptor and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth Hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6–8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.
doi:10.1016/j.neurobiolaging.2011.09.014
PMCID: PMC3266474  PMID: 22015312
Long-term potentiation; paired-pulse ratios; input-output curves; AMPA receptor; NMDA receptor
8.  Electrophysiological Characterization of AMPA and NMDA Receptors in Rat Dorsal Striatum 
The striatum receives glutamatergic afferents from the cortex and thalamus, and these synaptic transmissions are mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors. The purpose of this study was to characterize glutamate receptors by analyzing NMDA/AMPA ratio and rectification of AMPA and NMDA excitatory postsynaptic currents (EPSCs) using a whole-cell voltage-clamp method in the dorsal striatum. Receptor antagonists were used to isolate receptor or subunit specific EPSC, such as (DL)-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, ifenprodil, an NR2B antagonist, CNQX, an AMPA receptor antagonist and IEM-1460, a GluR2-lacking AMPA receptor blocker. AMPA and NMDA EPSCs were recorded at -70 and +40 mV, respectively. Rectification index was calculated by current ratio of EPSCs between +50 and -50 mV. NMDA/AMPA ratio was 0.20±0.05, AMPA receptor ratio of GluR2-lacking/GluR2-containing subunit was 0.26±0.05 and NMDA receptor ratio of NR2B/NR2A subunit was 0.32±0.03. The rectification index (control 2.39±0.27) was decreased in the presence of both APV and combination of APV and IEM-1460 (1.02±0.11 and 0.93±0.09, respectively). These results suggest that the major components of the striatal glutamate receptors are GluR2-containing AMPA receptors and NR2A-containing NMDA receptors. Our results may provide useful information for corticostriatal synaptic transmission and plasticity studies.
doi:10.4196/kjpp.2009.13.3.209
PMCID: PMC2766737  PMID: 19885039
Striatum; AMPA; Glutamate receptor; NMDA; Patch clamp
9.  Activation of EphA Receptors Mediates the Recruitment of the Adaptor Protein Slap, Contributing to the Downregulation of N-Methyl-d-Aspartate Receptors 
Molecular and Cellular Biology  2013;33(7):1442-1455.
Regulation of the activity of N-methyl-d-aspartate receptors (NMDARs) at glutamatergic synapses is essential for certain forms of synaptic plasticity underlying learning and memory and is also associated with neurotoxicity and neurodegenerative diseases. In this report, we investigate the role of Src-like adaptor protein (Slap) in NMDA receptor signaling. We present data showing that in dissociated neuronal cultures, activation of ephrin (Eph) receptors by chimeric preclustered eph-Fc ligands leads to recruitment of Slap and NMDA receptors at the sites of Eph receptor activation. Interestingly, our data suggest that prolonged activation of EphA receptors is as efficient in recruiting Slap and NMDA receptors as prolonged activation of EphB receptors. Using established heterologous systems, we examined whether Slap is an integral part of NMDA receptor signaling. Our results showed that Slap does not alter baseline activity of NMDA receptors and does not affect Src-dependent potentiation of NMDA receptor currents in Xenopus oocytes. We also demonstrate that Slap reduces excitotoxic cell death triggered by activation of NMDARs in HEK293 cells. Finally, we present evidence showing reduced levels of NMDA receptors in the presence of Slap occurring in an activity-dependent manner, suggesting that Slap is part of a mechanism that homeostatically modulates the levels of NMDA receptors.
doi:10.1128/MCB.01618-12
PMCID: PMC3624273  PMID: 23382070
10.  Selective Vulnerabilities of N-methyl-D-aspartate (NMDA) Receptors During Brain Aging 
N-methyl-D-aspartate (NMDA) receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within different brain regions. Spatial reference, passive avoidance, and working memory, as well as place field stability and expansion all involve NMDA receptors. Aged animals show deficiencies in these functions, as compared to young, and some studies have identified an association between age-associated changes in the expression of NMDA receptors and poor memory performance. A number of diet and drug interventions have shown potential for reversing or slowing the effects of aging on the NMDA receptor. On the other hand, there is mounting evidence that the NMDA receptors that remain within aged individuals are not always associated with good cognitive functioning. This may be due to a compensatory response of neurons to the decline in NMDA receptor expression or a change in the subunit composition of the remaining receptors. These studies suggest that developing treatments that are aimed at preventing or reversing the effects of aging on the NMDA receptor may aid in ameliorating the memory declines that are associated with aging. However, we need to be mindful of the possibility that there may also be negative consequences in aged individuals.
doi:10.3389/fnagi.2010.00011
PMCID: PMC2874396  PMID: 20552049
aging; NMDA receptor; glutamate; binding; subunits; LTP; memory; learning
11.  Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice 
Nature Communications  2013;4:2258.
The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning.
Motor cortex NMDA receptors have a key role in the acquisition of associative memories. Hasan et al. generate mice lacking NMDA receptor activity in the motor cortex and find that this impairs LTP, strengthening of synapses between somatosensory and motor cortices, and associative learning.
doi:10.1038/ncomms3258
PMCID: PMC3759079  PMID: 23978820
12.  AGAP3 and Arf6 Regulate Trafficking of AMPA Receptors and Synaptic Plasticity 
The Journal of Neuroscience  2013;33(31):12586-12598.
During NMDA receptor-mediated long-term potentiation (LTP), synapses are strengthened by trafficking AMPA receptors to the synapse through a calcium-dependent kinase cascade following activation of NMDA receptors. This process results in a long-lasting increase in synaptic strength that is thought to be a cellular mechanism for learning and memory. Over the past 20 years, many signaling pathways have been shown to be involved in the induction and maintenance of LTP including the MAPK cascade. However, the crucial link between NMDA receptors and the signaling cascades involved in AMPA receptor trafficking during LTP remains elusive. In this study, we aimed to identify and characterize NMDA receptor signaling proteins that link NMDA receptor activation to downstream signaling pathways that lead to trafficking of AMPA receptors. We have identified a novel NMDA receptor interacting signaling protein, AGAP3. AGAP3 contains multiple signaling domains, a GTPase-like domain, a pleckstrin homology domain, and an ArfGAP domain, and exists as a component of the NMDA receptor complex. In addition, we found that AGAP3 regulates NMDA receptor-mediated Ras/ERK and Arf6 signaling pathways during chemically induced LTP in rat primary neuronal cultures. Finally, knocking down AGAP3 expression leads to occlusion of AMPA receptor trafficking during chemically induced LTP. Together, AGAP3 is an essential signaling component of the NMDA receptor complex that links NMDA receptor activation to AMPA receptor trafficking.
doi:10.1523/JNEUROSCI.0341-13.2013
PMCID: PMC3728681  PMID: 23904596
13.  Kainate receptors and the induction of mossy fibre long-term potentiation. 
There is intense interest in understanding the molecular mechanisms involved in long-term potentiation (LTP) in the hippocampus. Significant progress in our understanding of LTP has followed from studies of glutamate receptors, of which there are four main subtypes (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), mGlu and kainate). This article summarizes the evidence that the kainate subtype of glutamate receptor is an important trigger for the induction of LTP at mossy fibre synapses in the CA3 region of the hippocampus. The pharmacology of the first selective kainate receptor antagonists, in particular the GLU(K5) subunit selective antagonist LY382884, is described. LY382884 selectively blocks the induction of mossy fibre LTP, in response to a variety of different high-frequency stimulation protocols. This antagonist also inhibits the pronounced synaptic facilitation of mossy fibre transmission that occurs during high-frequency stimulation. These effects are attributed to the presence of presynaptic GLU(K5)-subunit-containing kainate receptors at mossy fibre synapses. Differences in kainate receptor-dependent synaptic facilitation of AMPA and NMDA receptor-mediated synaptic transmission are described. These data are discussed in the context of earlier reports that glutamate receptors are not involved in mossy fibre LTP and more recent experiments using kainate receptor knockout mice, that argue for the involvement of GLU(K6) but not GLU(K5) kainate receptor subunits. We conclude that activation of presynaptic GLU(K5)-containing kainate receptors is an important trigger for the induction of mossy fibre LTP in the hippocampus.
doi:10.1098/rstb.2002.1216
PMCID: PMC1693169  PMID: 12740111
14.  Cingulate NMDA NR2B receptors contribute to morphine-induced analgesic tolerance 
Molecular Brain  2008;1:2.
Morphine is widely used to treat chronic pain, however its utility is hindered by the development of tolerance to its analgesic effects. While N-methyl-D-aspartate (NMDA) receptors are known to play roles in morphine tolerance and dependence, less is known about the roles of individual NMDA receptor subtypes. In this study, Ro 256981, an antagonist of the NMDA receptor subunit NR2B, was used to reduce the expression of analgesic tolerance to morphine. The mechanisms altered with chronic drug use share similarities with those underlying the establishment of long-tem potentiation (LTP) and behavioral memory. Since NMDA NR2B receptors in the anterior cingulate cortex (ACC) play roles in the establishment of LTP and fear memory, we explored their role in changes that occur in this region after chronic morphine. Both systemic and intra-ACC inhibition of NR2B in morphine-tolerant animals inhibited the expression of analgesic tolerance. Electrophysiological recordings revealed a significant increase in the NR2B component of NMDA receptor mediated excitatory postsynaptic currents (EPSCs), at both synaptic and extra-synaptic sites. However, there was no change in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated EPSCs. This study suggests that selective inhibition of NMDA NR2B receptors may prove useful in combating the development of analgesic tolerance to morphine and proposes a novel role for the ACC in opioid tolerance and morphine induced changes in synaptic plasticity.
doi:10.1186/1756-6606-1-2
PMCID: PMC2546399  PMID: 18803856
15.  Chronic inactivation of a neural circuit enhances LTP by inducing silent synapse formation 
Chronic inactivation of a neural network is known to induce homeostatic upregulation of synaptic strength, a form of synaptic plasticity that differs from Hebbian-type synaptic plasticity in that it is not input-specific, but involves all synapses of an individual neuron. However, it is unclear how homeostatic and Hebbian synaptic plasticity interact in the same neuron. Here we show that long-term potentiation (LTP) at Schaffer collateral-CA1 synapses is greatly enhanced in cultured mouse hippocampal slices after chronic (60 hour) network-activity blockade with tetrodotoxin (TTX). This increase in LTP is not due to an altered synaptic NMDA receptor composition or presynaptic function. Instead, we found that silencing neural network activity not only increases the abundance of both AMPA and NMDA receptors at existing synapses as previously described, but also promotes the presence of new glutamatergic synapses that contain only NMDA receptors – a class of synapses that are functionally silent due to the absence of AMPA receptors. Induction of LTP in TTX-treated neurons leads to insertion of AMPA receptors into the silent synapses, therefore “switching on” these silent synapses, which produces the observed enhancement of LTP magnitude. Our findings suggest that homeostatic synaptic plasticity manifests not only in the adjustment of the strength of existing synapses, but also in the modulation of new synapse formation/maintenance. Moreover, presence of new but functionally silent synapses enables more robust LTP to occur through rapid conversion of silent synapses to active synapses, resulting in a stronger input-specific modulation of synapses following prolonged network silencing.
doi:10.1523/JNEUROSCI.3880-12.2013
PMCID: PMC3804283  PMID: 23365245
homeostatic plasticity; AMPA receptor; synaptic scaling; silent synapse; LTP
16.  Slowly developing depression of N-methyl-D-aspartate receptor mediated responses in young rat hippocampi 
BMC Neuroscience  2004;5:26.
Background
Activation of N-methyl-D-aspartate (NMDA) type glutamate receptors is essential in triggering various forms of synaptic plasticity. A critical issue is to what extent such plasticity involves persistent changes of glutamate receptor subtypes and many prior studies have suggested a main role for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in mediating the effect. Our previous work in hippocampal slices revealed that, under pharmacological unblocking of NMDA receptors, both AMPA and NMDA receptor mediated responses undergo a slowly developing depression. In the present study we have further adressed this phenomenon, focusing on the contribution via NMDA receptors. Pharmacologically isolated NMDA receptor mediated excitatory postsynaptic potentials (EPSPs) were recorded for two independent synaptic pathways in CA1 area using perfusion with low Mg2+ (0.1 mM) to unblock NMDA receptors.
Results
Following unblocking of NMDA receptors, there was a gradual decline of NMDA receptor mediated EPSPs for 2–3 hours towards a stable level of ca. 60–70 % of the maximal size. If such an experimental session was repeated twice in the same pathway with a period of NMDA receptor blockade in between, the depression attained in the first session was still evident in the second one and no further decay occurred. The persistency of the depression was also validated by comparison between pathways. It was found that the responses of a control pathway, unstimulated in the first session of receptor unblocking, behaved as novel responses when tested in association with the depressed pathway under the second session. In similar experiments, but with AP5 present during the first session, there was no subsequent difference between NMDA EPSPs.
Conclusions
Our findings show that merely evoking NMDA receptor mediated responses results in a depression which is input specific, induced via NMDA receptor activation, and is maintained for several hours through periods of receptor blockade. The similarity to key features of long-term depression and long-term potentiation suggests a possible relation to these phenomena. Additionally, a short term potentiation and decay (<5 min) were observed during sudden start of NMDA receptor activation supporting the idea that NMDA receptor mediated responses are highly plastic.
doi:10.1186/1471-2202-5-26
PMCID: PMC517399  PMID: 15285786
17.  Copper Inhibits NMDA Receptor-Independent LTP and Modulates the Paired-Pulse Ratio after LTP in Mouse Hippocampal Slices 
Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release.
doi:10.4061/2011/864753
PMCID: PMC3199118  PMID: 22028985
18.  Synaptic Plasticity Deficits and Mild Memory Impairments in Mouse Models of Chronic Granulomatous Disease 
Molecular and Cellular Biology  2006;26(15):5908-5920.
Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-d-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91phox and p47phox, both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91phox and p47phox mutant mice have mild impairments in hippocampus-dependent memory. The gp91phox mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47phox mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD.
doi:10.1128/MCB.00269-06
PMCID: PMC1592752  PMID: 16847341
19.  Behavioral analysis of NR2C knockout mouse reveals deficit in working memory and acquisition of conditioned fear 
N -methyl-D-aspartate (NMDA) receptors play an important role in excitatory neurotransmission and mediate synaptic plasticity associated with learning and memory. NMDA receptors are composed of two NR1 and two NR2 subunits and the identity of the NR2 subunit confers unique electrophysiologic and pharmacologic properties to the receptor. The precise role of NR2C-containing receptors in vivo is poorly understood. We have performed a battery of behavioral tests on NR2C knockout/nβ-galactosidase knock-in mice and found no difference in spontaneous activity, basal anxiety, forced-swim immobility, novel object recognition, pain sensitivity and reference memory in comparison to wildtype counterparts. However, NR2C knockout mice were found to exhibit deficits in fear acquisition and working memory compared to wildtype mice. Deficit in fear acquisition correlated with lack of fear conditioning-induced plasticity at the thalamo-amygdala synapse. These findings suggest a unique role of NR2C-containing receptors in associative and executive learning representing a novel therapeutic target for cognitive deficits and mental disorders such as post-traumatic stress disorder.
doi:10.1016/j.nlm.2011.01.008
PMCID: PMC3432405  PMID: 21295149
NMDA; NR2C; knockout; fear acquisition; working memory
20.  Selective Cholinergic Depletion in Medial Septum Leads to Impaired Long Term Potentiation and Glutamatergic Synaptic Currents in the Hippocampus 
PLoS ONE  2012;7(2):e31073.
Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.
doi:10.1371/journal.pone.0031073
PMCID: PMC3280283  PMID: 22355337
21.  Neurotransmitter Roles in Synaptic Modulation, Plasticity and Learning in the Dorsal Striatum 
Neuropharmacology  2010;58(7):951-961.
The dorsal striatum is a large forebrain region involved in action initiation, timing, control, learning and memory. Learning and remembering skilled movement sequences requires the dorsal striatum, and striatal subregions participate in both goal-directed (action-outcome) and habitual (stimulus-response) learning. Modulation of synaptic transmission plays a large part in controlling input to as well as the output from striatal medium spiny projection neurons (MSNs). Synapses in this brain region are subject to short-term modulation, including allosteric alterations in ion channel function and prominent presynaptic inhibition. Two forms of long-term synaptic plasticity have also been observed in striatum, long-term potentiation (LTP) and long-term depression (LTD). LTP at glutamatergic synapses onto MSNs involves activation of NMDA-type glutamate receptors and D1 dopamine or A2A adenosine receptors. Expression of LTP appears to involve postsynaptic mechanisms. LTD at glutamatergic synapses involves retrograde endocannabinoid signaling stimulated by activation of metabotropic glutamate receptors (mGluRs) and D2 dopamine receptors. While postsynaptic mechanisms participate in LTD induction, maintained expression involves presynaptic mechanisms. A similar form of LTD has also been observed at GABAergic synapses onto MSNs. Studies have just begun to examine the roles of synaptic plasticity in striatal-based learning. Findings to date indicate that molecules implicated in induction of plasticity participate in these forms of learning. Neurotransmitter receptors involved in LTP induction are necessary for proper skill and goal-directed instrumental learning. Interestingly, receptors involved in LTP and LTD at glutamatergic synapses onto MSNs of the “indirect pathway” appear to have important roles in habit learning. More work is needed to reveal if and when synaptic plasticity occurs during learning and if so what molecules and cellular processes, both short- and long-term, contribute to this plasticity.
doi:10.1016/j.neuropharm.2010.01.008
PMCID: PMC2849868  PMID: 20096294
Long-term plasticity; Dopamine; Glutamate; Endocannabinoid; Instrumental learning; Skill Learning
22.  Repeated third trimester-equivalent ethanol exposure inhibits long-term potentiation in the hippocampal CA1 region of neonatal rats 
Alcohol (Fayetteville, N.Y.)  2010;44(3):283-290.
Developmental ethanol exposure damages the hippocampus, causing long-lasting learning and memory deficits. Synaptic plasticity mechanisms (e.g. long-term potentiation—LTP), contribute to synapse formation and refinement during development. We recently showed that acute ethanol exposure inhibits glutamatergic synaptic transmission and N-methyl-D-aspartate (NMDA) receptor-dependent LTP in the CA1 hippocampal region of postnatal day (P) 7–9 rats. The objective of this study was to further characterize the effect ethanol on LTP in the developing CA1 hippocampus during the third trimester-equivalent. To more closely model human ethanol exposure during this period, rat pups were exposed to ethanol vapor (2 or 4.5 g/dL in air; serum ethanol concentrations = 96.6 – 147.2 or 322 – 395.6 mg/dL) from P2–9 (4 hrs/day). Brain slices were prepared immediately after the end of the 4-hr exposure on P7–9 and extracellular electrophysiological recordings were performed 1–7 hrs later under ethanol-free conditions to model early withdrawal. LTP was not different than group-matched controls in the 96.6 – 147.2 mg/dL group; however, it was impaired in the 322 – 395.6 mg/dL group. Neither α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/NMDA receptor function nor glutamate release was affected in the 322 – 395.6 mg/dL ethanol exposure group. These data suggest that repeated in vivo exposure to elevated ethanol doses during the third trimester-equivalent period impairs synaptic plasticity, which may alter maturation of hippocampal circuits and ultimately contributeto the long-lasting cognitive deficits associated with fetal alcohol spectrum disorder.
doi:10.1016/j.alcohol.2010.03.001
PMCID: PMC2916030  PMID: 20488644
Fetal alcohol syndrome; development; plasticity; glutamate; synaptic
23.  Stress at Learning Facilitates Memory Formation by Regulating AMPA Receptor Trafficking Through a Glucocorticoid Action 
Neuropsychopharmacology  2009;35(3):674-685.
Stress and glucocorticoids (GCs) can facilitate memory formation. However, the molecular mechanisms mediating their effects are largely unknown. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) trafficking has been implicated in the changes in synaptic strength at central glutamatergic synapses associated with memory formation. In cell cultures, corticosterone has been shown to condition the synaptic trafficking of the AMPAR GluA2 subunit. In this study, we investigated the involvement of GluA2 trafficking in the facilitation of learning by stress. Using the water maze spatial task involving different stress levels, mice trained under more stressful conditions (water at 22°C) showed better learning and memory, and higher post-training corticosterone levels, than mice trained under lower stress (water at 30°C). Strikingly, this facilitated learning by stress was accompanied by enhanced synaptic expression of GluA2 AMPARs that was not observed in mice trained under less stressful conditions. Interfering with GC actions by injecting the GC synthesis inhibitor, metyrapone, blocked both the memory facilitation and the enhanced GluA2 trafficking induced by stressful learning. Intracerebroventricular infusion of the peptide, pep2m, that blocks GluA2 synaptic trafficking by interfering with the interaction between N-ethylmaleimide-sensitive factor and GluA2, impaired immediate performance at learning as well as long-term memory retrieval, supporting a causal role for GluA2 trafficking in stress-induced facilitation of spatial learning and memory. Evidence for the involvement of the neural cell adhesion molecule N-cadherin in interaction with GluA2 is also provided. These findings underscore a new mechanism whereby stress can improve memory function.
doi:10.1038/npp.2009.172
PMCID: PMC3055605  PMID: 19890264
stress; corticosterone; learning; memory; GluA2; mice
24.  GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity 
N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.
doi:10.1098/rstb.2013.0163
PMCID: PMC3843894  PMID: 24298164
NMDA receptor subunit; hippocampus; plasticity; learning
25.  Ionotropic Glutamate Receptors and Voltage-Gated Ca2+ Channels in Long-Term Potentiation of Spinal Dorsal Horn Synapses and Pain Hypersensitivity 
Neural Plasticity  2013;2013:654257.
Over the last twenty years of research on cellular mechanisms of pain hypersensitivity, long-term potentiation (LTP) of synaptic transmission in the spinal cord dorsal horn (DH) has emerged as an important contributor to pain pathology. Mechanisms that underlie LTP of spinal DH neurons include changes in the numbers, activity, and properties of ionotropic glutamate receptors (AMPA and NMDA receptors) and of voltage-gated Ca2+ channels. Here, we review the roles and mechanisms of these channels in the induction and expression of spinal DH LTP, and we present this within the framework of the anatomical organization and synaptic circuitry of the spinal DH. Moreover, we compare synaptic plasticity in the spinal DH with classical LTP described for hippocampal synapses.
doi:10.1155/2013/654257
PMCID: PMC3808892  PMID: 24224102

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