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Peter V Nguyen

Publications and source records attributed to Peter V Nguyen.

16 recordsLinked to original sources
PubMed2006

Recent advances in basic neurosciences and brain disease: from synapses to behavior.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29-31, 2007).

Behavior↗
PubMed2006

Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging.

The late-phase of long-term potentiation (L-LTP) in hippocampal area CA1 requires gene expression and de novo protein synthesis but it is expressed in an input-specific manner. The 'synaptic tag' theory proposes that gene products can only be captured and utilized at synapses that have been 'tagged' by previous activity. The mechanisms underlying synaptic tagging, and its activity dependence, are largely undefined. Previously, we reported that low-frequency stimulation (LFS) decreases the stability of L-LTP in a cell-wide manner by impairing synaptic tagging. We show here that a phosphatase inhibitor, okadaic acid, blocked homosynaptic and heterosynaptic inhibition of L-LTP by prior LFS. In addition, prior LFS homosynaptically and heterosynaptically impaired chemically induced synaptic facilitation elicited by forskolin/3-isobutyl-1-methylxanthine, suggesting that there is a cell-wide dampening of cAMP/protein kinase A (PKA) signaling concurrent with phosphatase activation. We propose that prior LFS impairs expression of L-LTP by inhibiting synaptic tagging through its actions on the cAMP/PKA pathway. In support of this notion, we show that hippocampal slices from transgenic mice that have genetically reduced hippocampal PKA activity display impaired synaptic capture of L-LTP. An inhibitor of PKA, KT-5720, also blocked synaptic capture of L-LTP. Moreover, pharmacological activation of the cAMP/PKA pathway can produce a synaptic tag to capture L-LTP expression, resulting in persistent synaptic facilitation. Collectively, our results show that PKA is critical for synaptic tagging and for input-specific L-LTP. PKA-mediated signaling can be constrained by prior episodes of synaptic activity to regulate subsequent L-LTP expression and perhaps control the integration of multiple synaptic events over time.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Homosynaptic and heterosynaptic inhibition of synaptic tagging and capture of long-term potentiation by previous synaptic activity.

Long-term potentiation (LTP) is an enhancement of synaptic strength that may contribute to information storage in the mammalian brain. LTP expression can be regulated by previous synaptic activity, a process known as "metaplasticity." Cell-wide occurrence of metaplasticity may regulate synaptic strength. However, few reports have demonstrated metaplasticity at synapses that are silent during activity at converging synaptic inputs. We describe a novel form of cell-wide metaplasticity in hippocampal area CA1. Low-frequency stimulation (LFS) decreased the stability of long-lasting LTP ["late" LTP (L-LTP)] induced later at the same inputs (homosynaptic inhibition) and at other inputs converging on the same postsynaptic cells (heterosynaptic inhibition). Significantly, heterosynaptic inhibition of L-LTP also occurred across basal and apical dendrites ("heterodendritic" inhibition). Because transient early LTP (E-LTP) was not affected by previous LFS, we examined the effects of LFS on the consolidation of E-LTP to L-LTP. The duration of E-LTP induced at one set of inputs can be extended by capturing L-LTP-associated gene products generated by previous activity at other inputs to the same postsynaptic neurons. LFS applied homosynaptically or heterosynaptically before L-LTP induction did not impair synaptic capture by subsequent E-LTP stimulation, suggesting that LFS does not impair L-LTP-associated transcription. In contrast, LFS applied just before E-LTP (homosynaptically or heterosynaptically) prevented synaptic tagging, and capture of L-LTP expression. Thus, LFS inhibits synaptic tagging to impair expression of subsequent L-LTP. Such anterograde inhibition represents a novel way in which synaptic activity can regulate the expression of future long-lasting synaptic plasticity in a cell-wide manner.

Animals↗
PubMed2005

Beta-adrenergic receptor activation facilitates induction of a protein synthesis-dependent late phase of long-term potentiation.

Long-term potentiation (LTP) is activity-dependent enhancement of synaptic strength that can critically regulate long-term memory storage. Like memory, LTP exhibits at least two mechanistically distinct temporal phases. Early LTP (E-LTP) does not require protein synthesis, whereas the late phase of LTP (L-LTP), like long-term memory, requires protein synthesis. Hippocampal beta-adrenergic receptors can regulate expression of both E-LTP and long-term memory. Although beta-adrenergic receptor activation enhances the ability of subthreshold stimuli to induce E-LTP, it is unclear whether such activation can facilitate induction of L-LTP. Here, we use electrophysiological recording methods on mouse hippocampal slices to show that when synaptic stimulation that is subthreshold for inducing L-LTP is paired with beta-adrenergic receptor activation, the resulting LTP persists for over 6 h in area CA1. Like L-LTP induced by multiple trains of high-frequency electrical stimulation, this LTP requires protein synthesis. Unlike tetanus-induced L-LTP, however, L-LTP induced by beta-adrenergic receptor activation during subthreshold stimulation appears to involve dendritic protein synthesis but not somatic transcription. Maintenance of this LTP also requires activation of extracellular signal-regulated kinases (ERKs). Thus, beta-adrenergic receptor activation elicits a type of L-LTP that requires translation and ERK activation but not transcription. This form of L-LTP may be a cellular mechanism for facilitation of behavioral long-term memory during periods of heightened emotional arousal that engage the noradrenergic modulatory system.

Adrenergic beta-Agonists↗
PubMed2005

Mouse models of impaired fear memory exhibit deficits in amygdalar LTP.

Inbred mouse strains have different genetic backgrounds that can result in impairments of synaptic plasticity and memory. They are valuable models for probing the mechanisms of memory impairments. We examined fear memory in several inbred strains, along with synaptic plasticity that may underlie fear memory. Long-term potentiation (LTP) is a form of activity-dependent synaptic plasticity that is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired contextual or cued fear memory may have selective LTP deficits in different hippocampal subregions, or in the amygdala. We measured fear memory and its extinction in five inbred strains: C57BL/6NCrlBR (B6), A/J, BALB/cByJ (BALB), C57BL/10J (B10), and SM/J (SM). We also measured LTP in the basolateral amygdala and in the hippocampal Schaeffer collateral-commissural (SC) and medial perforant pathways (MPP). All strains exhibited intact contextual fear memory 24 h post-training, but cued fear memory was impaired in strains A/J, BALB, and SM. At 1 h post-training, both contextual and cued fear memory deficits were more widespread: all strains except for B6 and B10 showed impairments of both types of memory. Contextual fear extinction was impaired in BALB and SM. We found that amygdalar LTP was reduced in strains A/J and BALB, but SC LTP was intact in all strains (except for a selective multi-train LTP impairment in BALB). MPPLTP was similar in all five strains. Thus, reduced amygdalar LTP is correlated with impaired cued fear memory in strains A/J and BALB. Also, hippocampal SC LTP is more strongly correlated with 24-h (long-term) than with 1-h (short-term) contextual fear memory. In this first conjoint study of amygdala-dependent memory and amygdalar LTP in inbred mice, we identified specific hippocampal and amygdalar LTP deficits that correlate with fear memory impairments. These deficits should be considered when selecting inbred strains for genetic modification.

Amygdala↗
PubMed2005

Impaired fear memories are correlated with subregion-specific deficits in hippocampal and amygdalar LTP.

Inbred mouse strains have different genetic backgrounds that likely influence memory and long-term potentiation (LTP). LTP, a form of synaptic plasticity, is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired fear memory may have selective LTP deficits in different hippocampal subregions or in the amygdala. The authors assessed fear memory in 4 inbred strains: C57BL/6NCrlBR (B6), 129S1/SvImJ (129), C3H/HeJ (C3H), and DBA/2J (D2). The authors also measured LTP in the hippocampal Schaeffer collateral (SC) and medial perforant pathways (MPP) and in the basolateral amygdala. Contextual and cued fear memory, and SC and amygdalar LTP, were intact in B6 and 129, but all were impaired in C3H and D2. MPP LTP was similar in all 4 strains. Thus, SC, but not MPP, LTP correlates with hippocampus-dependent contextual memory expression, and amygdalar LTP correlates with amygdala-dependent cued memory expression, in these inbred strains.

Amygdala↗
PubMed2005

CREB, synapses and memory disorders: past progress and future challenges.

In neurons, appropriate long-term adaptive responses to changes in the environment require the conversion of extracellular stimuli into discrete intracellular signals. Many of these signals involve the regulation of gene expression. The cAMP responsive element binding protein (CREB) is a nuclear transcription factor that modulates transcription of genes containing cAMP responsive elements (CRE sites) in their promoters. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Numerous studies on invertebrates and vertebrates demonstrate that CREB is critical for long-term memory. Here, we review the key features of CREB-dependent transcription and critically evaluate the data examining the roles of CREB in different forms of plasticity, including long-term memory in mammals. Because learning and memory have been linked to specific types of synaptic plasticity in several species, we also review studies on the role of CREB in long-term facilitation in Aplysia and in hippocampal long-term potentiation (LTP). Several human cognitive disorders have been linked to alterations of CREB-regulated gene expression. Therefore, we explore the possibility of targeting CREB function in developing novel treatment strategies. Finally, we highlight areas of research on CREB that are ripe for further advancement.

Animals↗
PubMed2003

Protein synthesis is required for synaptic immunity to depotentiation.

De novo protein synthesis and transcription are necessary for the expression of long-lasting synaptic potentiation [long-term potentiation (LTP)] in hippocampal area CA1 and for the consolidation of long-term memory. The stability of LTP and its longevity require macromolecular synthesis at later stages, but a specific role for early protein synthesis has not been identified. Using electrophysiological recording methods in mouse hippocampal slices, we show that multiple trains of high-frequency stimulation provide immediate synaptic immunity to depotentiation. This immunity to depotentiation is dependent on the amount of synaptic stimulation used to induce LTP, it is input specific, and it is prevented by inhibitors of protein synthesis. We propose that local translation mediates input-specific synaptic immunity against depotentiation. We also present evidence suggesting that, in addition to translation, products of transcription can provide cell-wide immunity to depotentiation via heterosynaptic transfer of synaptic immunity between distinct pathways in area CA1. Protein synthesis and transcription may importantly regulate long-term storage of information by conferring synaptic immunity to depotentiation at previously potentiated synapses.

Animals↗
PubMed2003

Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase blocks expression of long-lasting synaptic potentiation in hippocampal neurons.

Multiple trains of high-frequency synaptic stimulation evoke long-term potentiation (LTP) of synaptic transmission in hippocampal area CA1, which has been correlated with hippocampal long-term memory and requires the activation of cAMP-dependent protein kinase (PKA). To assess whether postsynaptic PKA is necessary for the expression of LTP, we made prolonged whole-cell voltage-clamp recordings from CA1 pyramidal neurons in mouse hippocampal slices during postsynaptic infusion of cell-impermeant modulators of PKA. Repeated stimulation (four 100 Hz trains at 5 min intervals) of the Schaffer collateral pathway increased synaptically evoked EPSCs for up to 2 hr. The postsynaptic infusion of either a cell-permeant PKA inhibitor (Rp-cAMPS) or a cell-impermeant PKA inhibitor (PKI(6-22)) did not alter post-tetanic peak potentiation, but it caused significant decay of EPSCs to pretetanization amplitudes within 1.5 hr. In contrast, postsynaptic infusion of PKI(6-22) did not alter a more modest, decaying form of LTP evoked by a single 100 Hz train. Paired-pulse facilitation was unchanged during most of the duration of LTP, suggesting that postsynaptic mechanisms, including PKA activation, are involved in the expression of LTP induced by multitrain stimulation. The postsynaptic infusion of a constitutively active isoform of the PKA catalytic subunit (Calpha) into CA1 pyramidal neurons increased EPSC sizes to elicit long-lasting synaptic facilitation. Thus, mimicking the activation of PKA in postsynaptic CA1 pyramidal neurons is sufficient for inducing persistent synaptic facilitation. Activation of apostsynaptic PKA is necessary for the expression of LTP in CA1 pyramidal neurons and is sufficient for initiating persistent synaptic facilitation.

Animals↗
PubMed2003

Temporal spacing of synaptic stimulation critically modulates the dependence of LTP on cyclic AMP-dependent protein kinase.

Genetic and electrophysiological experiments have defined an important role for cAMP-dependent protein kinase (PKA) in certain forms of long-term potentiation (LTP). However, the characteristics of stimulation that are critical for regulating the PKA-dependence of LTP have not been clearly defined. In the present study, we have used PKA mutant mice (R(AB) transgenic mice), which have reduced PKA activity in neurons within the hippocampus, to explore the role of temporal spacing of synaptic stimulation in regulating the PKA-dependence of LTP. The time interval between successive bursts of electrical stimulation was varied while keeping constant the total number of stimulus pulses. LTP induced by temporally spaced tetraburst synaptic stimulation was impaired in the Schaeffer collateral pathway of hippocampal slices from R(AB) mutant mice. In contrast, LTP induced by temporally compressed tetraburst stimulation was normal in slices from R(AB) mutants, and its long-term maintenance was not significantly affected by bath application of KT-5720, an inhibitor of catalytic subunits of PKA. In slices from wildtype mice, LTP induced by spaced tetraburst stimulation was significantly attenuated by KT-5720. These genetic and pharmacological experiments show that LTP induced by these compressed patterns of stimulation does not require PKA activation. Thus, altering the temporal spacing of synaptic stimulation per se critically modulates the PKA-dependence of hippocampal LTP. PKA-dependent LTP is selectively recruited by temporally spaced, multiburst synaptic stimulation.

Animals↗
PubMed2002

Selective modification of short-term hippocampal synaptic plasticity and impaired memory extinction in mice with a congenitally reduced hippocampal commissure.

The hippocampus is critical for forming new long-term memories, but the contributions of the hippocampal commissure (HC) to memory function and hippocampal synaptic plasticity are unclear. To shed light on this issue, we characterized behavioral memory and hippocampal synaptic plasticity in two inbred mouse strains. BALB/cWah1 mice display a range of corpus callosal defects and an intact HC, whereas 9XCA/Wah mice exhibit a complete absence of corpus callosum and a greatly reduced HC. No differences between strains were found in long-term potentiation (LTP) within two synaptic pathways in hippocampal slices. However, paired-pulse facilitation was deficient in area CA1 of slices from 9XCA/Wah, and it was rescued by decreasing extracellular [Ca2+], suggesting that presynaptic calcium dynamics may be altered in this strain. In addition, contextual fear extinction was impaired in 9XCA/Wah mice, but performance on cued fear extinction and on 24 hr memory tests for cued and contextual fear conditioning were not significantly different between strains. Thus, an intact HC is critical for normal extinction of contextual fear. Intact interhemispheric connectivity is not required for acquisition or expression of cued and contextual fear conditioning. LTP was normal in slices from mice that lacked an intact HC, and this was correlated with normal performance on fear conditioning tests. In contrast, impaired short-term synaptic plasticity was correlated with defective contextual memory extinction in mice lacking an intact HC. Thus, the HC in mice is vital for particular aspects of memory function and for short-term synaptic modification in specific hippocampal circuits.

Agenesis of Corpus Callosum↗
PubMed2002

Genetic and pharmacological demonstration of a role for cyclic AMP-dependent protein kinase-mediated suppression of protein phosphatases in gating the expression of late LTP.

Protein kinases and phosphatases play antagonistic roles in regulating hippocampal long-term potentiation (LTP), with kinase inhibition and phosphatase activation both impairing LTP. The late phase of LTP (L-LTP) requires activation of cAMP-dependent protein kinase (PKA) for its full expression. One way in which PKA may critically modulate L-LTP is by relieving an inhibitory constraint imposed by protein phosphatases. Using mutant PKA mice [R(AB) transgenic mice] that have genetically reduced hippocampal PKA activity, we show that deficient L-LTP in area CA1 of mutant hippocampal slices is rescued by acute application of two inhibitors of protein phosphatase-1 and protein phosphatase-2A (PP1/2A) (okadaic acid and calyculin A). Furthermore, synaptic facilitation induced by forskolin, an adenylyl cyclase activator, was impaired in R(AB) transgenics and was also rescued by a PP1/2A inhibitor in mutant slices. Inhibition of PP1/2A did not affect early LTP (E-LTP) or basal synaptic transmission in mutant and wildtype slices. Our data show that genetic inhibition of PKA impairs L-LTP by reducing PKA-mediated suppression of PP1/2A.

Animals↗
PubMed2002

Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training.

Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.

Animals↗
PubMedDate not supplied

"Silent" metaplasticity of the late phase of long-term potentiation requires protein phosphatases.

The late phase of long-term potentiation (L-LTP) is correlated with some types of long-term memory, but the mechanisms by which L-LTP is modulated by prior synaptic activity are undefined. Activation of protein phosphatases by low-frequency stimulation (LFS) given before induction of L-LTP may significantly modify L-LTP. Using cellular electrophysiological recording methods in mouse hippocampal slices, we show that LFS given before induction of L-LTP inhibited L-LTP in an activity-dependent manner without affecting either basal synaptic strength or the early phase of LTP (E-LTP). This anterograde inhibitory effect of LFS was persistent, required N-methyl-D-aspartate (NMDA) receptor activation, and was blocked by inhibitors of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). These data indicate that certain patterns of LFS can activate PP1 and/or PP2A, and that long-lasting activation of these phosphatases by prior LFS can suppress the subsequent expression of L-LTP without affecting E-LTP. Because this inhibition of L-LTP is caused by prior synaptic activity that, alone, produced no net effect on synaptic efficacy, we suggest that this is a "silent" form of metaplasticity that may influence long-term information storage by modulating the capacity of synapses to express L-LTP after repeated bouts of activity.

Animals↗