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PubMed2006

Stable competitive dynamics emerge from multispike interactions in a stochastic model of spike-timing-dependent plasticity.

In earlier work we presented a stochastic model of spike-timing-dependent plasticity (STDP) in which STDP emerges only at the level of temporal or spatial synaptic ensembles. We derived the two-spike interaction function from this model and showed that it exhibits an STDP-like form. Here, we extend this work by examining the general n-spike interaction functions that may be derived from the model. A comparison between the two-spike interaction function and the higher-order interaction functions reveals profound differences. In particular, we show that the two-spike interaction function cannot support stable, competitive synaptic plasticity, such as that seen during neuronal development, without including modifications designed specifically to stabilize its behavior. In contrast, we show that all the higher-order interaction functions exhibit a fixed-point structure consistent with the presence of competitive synaptic dynamics. This difference originates in the unification of our proposed "switch" mechanism for synaptic plasticity, coupling synaptic depression and synaptic potentiation processes together. While three or more spikes are required to probe this coupling, two spikes can never do so. We conclude that this coupling is critical to the presence of competitive dynamics and that multispike interactions are therefore vital to understanding synaptic competition.

Action Potentials↗
PubMed2006

Inhibition of glutamatergic activation of extracellular signal-regulated protein kinases in hippocampal neurons by the intravenous anesthetic propofol.

BACKGROUND: Intravenous anesthetics cause amnesia, but the underlying molecular mechanisms are poorly understood. Recent studies reveal a significant role of extracellular signal-regulated protein kinases (ERKs) in controlling synaptic plasticity and memory formation. As a major synapse-to-nucleus superhighway, ERK transmits N-methyl-D-aspartate (NMDA) receptor signals to inducible transcriptional events essential for NMDA receptor-dependent forms of synaptic plasticity and memory. This study investigated the role of the widely used intravenous anesthetic propofol in regulating NMDA receptor-dependent ERK phosphorylation. METHODS: The possible effect of propofol on NMDA receptor-mediated ERK phosphorylation was detected in cultured rat hippocampal neurons with Western blot analysis. RESULTS: The authors found that propofol at clinical relevant concentrations (1-10 microm) reduced NMDA receptor-mediated ERK phosphorylation. This reduction was independent of gamma-aminobutyric acid transmission. The inhibition of the NMDA receptor seems to contribute to the effect of propofol on NMDA-stimulated ERK phosphorylation, because propofol reduced constitutive NMDA receptor NR1 subunit phosphorylation and impaired NMDA receptor-mediated Ca influx. Furthermore, by inhibiting the ERK pathway, propofol blocked NMDA receptor-dependent activation of two key transcription factors, Elk-1 and cyclic adenosine monophosphate response element-binding protein (CREB), and, as a result, attenuated Elk-1/CREB-dependent reporter gene (c-Fos) expression. CONCLUSIONS: These results suggest that propofol possesses the ability to inhibit NMDA receptor activation of the ERK pathway and subsequent transcriptional activities in hippocampal neurons. These findings indicate a new avenue to explore a transcription-dependent mechanism that may underlie anesthetic interference with synaptic plasticity related to amnesic properties of intravenous anesthetics.

Anesthetics, Intravenous↗
PubMed2000

Trk B signalling controls LTP but not LTD expression in the developing rat visual cortex.

Neurotrophins have been suggested to act as liaison molecules between activity-dependent synaptic plasticity and the establishment of patterns of synaptic connectivity during postnatal developmental in different brain areas, including the visual cortex. In particular, recent studies have shown that Trk B ligands are involved in the formation of the ocular dominance columns during postnatal development. Here, we examined the contribution of endogenous Trk B activation to the regulation of different forms of synaptic plasticity including long-term potentiation (LTP), long-term depression (LTD) and LTP after LTD in the developing visual cortex. Rat cortical slices were incubated with a soluble form of Trk B receptor (TrkB IgG) preventing Trk B activation by endogenous ligands. LTP expression was also studied at P23 (postnatal), when the expression of brain-derived neurotrophic factor (BDNF) reaches a peak and the LTP expression is normally downregulated. The present results demonstrate that Trk B activation is required for the long-term maintenance, > 30 min, of both LTP and LTP after LTD at P17. At P23, a higher concentration of TrkB IgG was necessary to impair LTP. In contrast, neither amplitude nor duration of LTD were affected by Trk B ligands blockade. Taken together, these results indicate that endogenous Trk B ligands are necessary for the expression of LTP but not LTD at a critical time during postnatal cortical development.

Animals↗
PubMed1997

Cyclic AMP-dependent protein kinase and protein kinase C phosphorylate N-methyl-D-aspartate receptors at different sites.

Ca2+ influx through N-methyl-D-aspartate (NMDA)-type glutamate receptors plays a pivotal role in synaptic plasticity during brain development as well as in mature brain. Cyclic AMP-dependent protein kinase (PKA) and members of the protein kinase C (PKC) family are also essential for various forms of synaptic plasticity and regulate the activity of different ion channels including NMDA and non-NMDA receptors. We now demonstrate that PKA and various PKC isoforms phosphorylate the NMDA receptor in vitro. The stoichiometry of [32P]phosphate incorporation per [3H]MK-801 binding site is greater than 1 for both PKA and PKC. Double immunoprecipitation experiments show that all three NMDA receptor subunits that are prevalent in the cortical structures, NR1, NR2A, and NR2B, are substrates for PKA as well as PKC. Two-dimensional phosphopeptide mapping reveals that the major phosphorylation sites for PKA and PKC differ for all three subunits. We provide evidence that some if not most of these sites are phosphorylated in the central nervous system of rats in vivo. The results presented in this article together with earlier electrophysiological experiments demonstrating that PKA and PKC activation increases the activity of NMDA receptors indicate that NMDA receptor potentiation can be mediated by direct phosphorylation by PKA and PKC. Collectively, these results strongly suggest that NMDA receptor functions such as control of neuronal development or expression of synaptic plasticity are modulated by PKA- and PKC-mediated phosphorylation of NMDA receptors.

Adenosine Triphosphate↗
PubMed2000

Stable Hebbian learning from spike timing-dependent plasticity.

We explore a synaptic plasticity model that incorporates recent findings that potentiation and depression can be induced by precisely timed pairs of synaptic events and postsynaptic spikes. In addition we include the observation that strong synapses undergo relatively less potentiation than weak synapses, whereas depression is independent of synaptic strength. After random stimulation, the synaptic weights reach an equilibrium distribution which is stable, unimodal, and has positive skew. This weight distribution compares favorably to the distributions of quantal amplitudes and of receptor number observed experimentally in central neurons and contrasts to the distribution found in plasticity models without size-dependent potentiation. Also in contrast to those models, which show strong competition between the synapses, stable plasticity is achieved with little competition. Instead, competition can be introduced by including a separate mechanism that scales synaptic strengths multiplicatively as a function of postsynaptic activity. In this model, synaptic weights change in proportion to how correlated they are with other inputs onto the same postsynaptic neuron. These results indicate that stable correlation-based plasticity can be achieved without introducing competition, suggesting that plasticity and competition need not coexist in all circuits or at all developmental stages.

Action Potentials↗
PubMed2005

Effects of Na+-Ca2+ exchanger activity on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate-induced Ca2+ influx in cerebellar Purkinje neurons.

Variations in intracellular calcium activity ([Ca2+]i) play crucial roles in information processing in Purkinje neurons such as synaptic plasticity. Although Na+-Ca2+ exchanger (NCX) has been shown to participate in the regulation of homeostasis and secretion in neuronal cells, the physiological role of NCX in Purkinje neurons, such as a role in cerebellar synaptic plasticity, is not well understood. NCX in acutely dissociated rat Purkinje neurons was identified by double staining with anti-calbindin D-28k antibody and anti-NCX antibody. The physiological activity of NCX was examined by measuring transient intracellular Ca2+ changes resulting from the Ca2+ influx via reverse mode of NCX (with 0 mM Na+/2.5 mM Ca2+ solutions) and the efflux via the forward mode of NCX (with 140 mM Na+/0 mM Ca2+ solutions). This transient increase in Ca2+ concentration was not elicited in the cells pretreated with NCX antisense oligodeoxynucleotides. And the Ca2+ influx resulting from the reverse mode of NCX was significantly reduced by 2-[2-[4-(4-nitrobenyloxy) phenyl] ethyl] isothiourea methanesulfonate, while the Ca2+ efflux via forward mode was inhibited by bepridil. The physiological role of NCX in synaptic function was studied by measuring Ca2+ transients induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolone-propionate (AMPA) receptor activation. This AMPA-evoked response was decreased with the inhibition of NCX forward mode and also, to less degree, with the inhibition of reverse mode. In antisense oligodeoxynucleotides pretreated cells, the AMPA-evoked response was also reduced, as was the case in NCX-inhibitor treated cells. The inhibition of NCX activity had depressant effects on Ca2+ transients induced by AMPA receptor activation. These results suggest that NCX plays a physiological role in modulating the activity of cerebellar Purkinje neurons, such as synaptic plasticity, via interaction with AMPA receptors in Purkinje neurons.

Agatoxins↗
PubMedDate not supplied

Plasticity of GABAergic synapses in the neonatal rat hippocampus.

While the development and plasticity of excitatory synaptic connections have been studied into detail, little is known about the development of inhibitory synapses. As proposed for excitatory synapses, recent studies have indicated that activity-dependent forms of synaptic plasticity, such as long-term potentiation and long-term depression, may play a role in the establishment of functional inhibitory synaptic connections. Here, I review these different forms of plasticity and focus on their possible role in the developing neuronal network.

Animals↗
PubMed2004

Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1.

Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a(-/-)) are characterized by deficient short- and long-term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a(-/-) mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic-like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of explorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O-maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a(-/-) mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a-dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavioral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a(-/-) mice bore no relation to the behavioral changes as observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed.

Animals↗
PubMed2003

Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1.

The inhibitory activity of gamma-aminobutyric acid (GABA) is considered critical in setting the conditions for synaptic plasticity, and many studies support an important role of GABA in the suppression of nociceptive transmission in the dorsal horn. Consequently, any injury-induced modification of the GABA action has the potential to critically modify spinal synaptic plasticity. We have previously reported that chronic constriction injury of the sciatic nerve was accompanied by long-lasting potentiation of superficial spinal dorsal horn field potentials following high-frequency tetanus. In this study we examined whether the GABA-A receptor agonist muscimol would modify post-tetanic responses in rats with chronic constriction injury. In animals exhibiting maximal thermal hyperalgesia as one sign of neuropathic pain 7 days after loose ligation of the sciatic nerve, spinal application of muscimol (5, 10 or 20 microg) before the high-frequency (50 Hz) tetanus produced a long-lasting depression (rather than potentiation) of spinal dorsal horn field potentials. In separate but related Western immunoblot experiments, we also established that the chronic constriction injury was accompanied by significant decreases in the content of the GABA transporter GAT-1. These data demonstrated that GABA-A receptor agonists may effectively influence the expression of long-lasting synaptic plasticity in the spinal dorsal horn, and that an injury-induced loss in GABA transporter content may have contributed to a depletion of GABA from its terminals within the spinal dorsal horn. These data lent further support to the notion that the loss of GABA inhibition may have important consequences for the development of neuropathic pain.

Action Potentials↗
PubMed2006

Plasticity-related regulation of the hippocampal proteome.

Plasticity of glutamatergic synapses is considered to be a pivotal mechanism underlying the ability of the CNS to re-configure its neural circuits. A large number of studies have focused on investigating how individual proteins, biochemical pathways and structural processes alter both the induction and maintenance of synaptic plasticity. However, it is likely that synaptic plasticity involves temporally and spatially coordinated regulation of multiple protein complexes within the activated neural circuit. By using a global proteomics-based approach we have now been able to reveal that highly diverse protein classes exhibit altered expression in response to both the activation of glutamate receptors and the induction of long-term potentiation (LTP) of glutamatergic synaptic strength in the hippocampus; a brain area where plastic synaptic modification is believed to be key to cognitive processes, such as spatial learning. Of the 2946 resolvable protein spots detected in this study, 79 (2.7%) were significantly altered in abundance in response to 100 microM glutamate application (all P < 0.05). The majority (56 out of 79) of these changes were due to the activation of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. Likewise, the induction of LTP was associated with an altered abundance of 2.4% of the detectable proteome during the early (10 min) phase and 1.7% during the late (4 h) phase of its development. Observed changes in temporal and protein class-specific patterns of expression depict a widespread shift from metabolic to structural protein alteration as the plasticity process matures.

2-Amino-5-phosphonovalerate↗
PubMed1987

Testosterone-induced plasticity of synaptic inputs to adult mammalian motoneurons.

The effects of testosterone administration on penile reflexes, and on the motoneurons of the spinal nucleus of the bulbocavernosus which innervate perineal muscles involved in these reflexes, were investigated in castrated male rats. Penile reflexes were restored following 48 h of testosterone administration initiated 6 weeks after castration. The amount of synaptic input to the identified motoneurons was increased following short term testosterone treatment, compared to that seen in animals receiving no testosterone, albeit to a lesser extent than that seen in animals receiving long term testosterone treatment. This increase in synaptic inputs in the short term testosterone group occurred despite the lack of an increase in somatic area. Thus, plasticity of the synaptic input to these neurons, as well as recovery of penile reflexes, occurred as a result of alterations in the hormonal state of the animal, and such changes occurred relatively rapidly.

Afferent Pathways↗
PubMed2003

The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence.

There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder. This continuous mild activation may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg(2+) ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg(2+) concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine-an uncompetitive NMDA receptor antagonists with features of an 'improved' Mg(2+) (voltage-dependency, kinetics, affinity)-attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 microM). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium.

Aged↗
PubMed1987

The effect of chronic hydergine treatment on the plasticity of synaptic junctions in the dentate gyrus of aged rats.

The number of synapses (Nv), the surface density of contact zones (Sv) as well as the average size (S) of E-PTA stained synapses in the supragranular layer of the dentate gyrus from adult (12 months), old (30 month), and Hydergine-treated old (30 months) rats were measured by using quantitative morphometric techniques. In old animals, Nv and Sv were significantly reduced, whereas S was significantly increased as compared with the values in adult rats. Hydergine (Codergocrine mesylate) treatment of old animals (3 mg/Kg/day for 4 weeks) influenced these three parameters, differentially. The Sv in aged animals receiving Hydergine, relative to that in untreated old rats, was significantly increased; the number and size of synapses in the treated old rats were significantly higher and smaller, respectively, than that in old controls. We interpret the present findings to indicate a modulating effect of Hydergine on the morphological plasticity of synaptic junctions in the dentate gyrus of aged rats.

Aging↗
PubMed2006

Enhancement of hippocampal long-term potentiation induced by cocaine self-administration is maintained during the extinction of this behavior.

Drug addiction may involve learning and memory processes requiring the participation of hippocampal formation. One of the best studied examples of hippocampal synaptic plasticity is the long-term potentiation (LTP) which usually occurs when hippocampal synapses are stimulated with high-frequency stimulation. The aim of this work has been to study the effect of extinction of cocaine self-administration behavior on synaptic plasticity in rat hippocampal slices. LTP was induced using a tetanization paradigm consisting of a single train of high-frequency (100 Hz) stimulation for one second. This tetanization protocol evoked a greater and more perdurable LTP in slices obtained after 10 days of extinction of cocaine self-administration (1 mg/kg/injection) than that elicited in slices from saline self-administering (0.9% NaCl) animals. In addition, this LTP facilitation in animals which have followed the cocaine self-administration extinction protocol was very similar to that obtained in slices from cocaine self-administering animals. These results suggest that chronic cocaine self-administration induces enduring neuroadaptive changes in hippocampal synaptic plasticity which last even after the extinction of this behavior and that they may be involved in cocaine dependence.

Animals↗
PubMed2000

Chronic failure in the maintenance of long-term potentiation following fluid percussion injury in the rat.

Traumatic brain injury (TBI) can produce chronic cognitive learning/memory deficits that are thought to be mediated, in part, by impaired hippocampal function. Experimentally induced TBI is associated with deficits in hippocampal synaptic plasticity (long-term potentiation, or LTP) at acute post-injury intervals but plasticity has not been examined at long-term survival periods. The present study was conducted to assess the temporal profile of LTP after injury and to evaluate the effects of injury severity on plasticity. Separate groups of rats were subjected to mild (1.1-1.4 atm), moderate (1.8-2.1 atm), or severe (2.2-2.7 atm) fluid percussion (FP) injury (or sham surgery) and processed for hippocampal electrophysiology in the first or eighth week after injury. LTP was defined as a lasting increase in field excitatory post-synaptic potential (fEPSP) slope in area CA1 following tetanic stimulation of the Schaffer collaterals. The fEPSP slope was measured for 60 min after tetanus. Assessment of LTP at the acute interval (6 days) revealed modest peak slope potentiation values (129-139%), which declined in each group (including sham) over the hour-long recording session and did not differ between groups. Eight weeks following injury, slices from all groups exhibited robust maximal potentiation (134-147%). Levels of potentiation among groups were similar at the 5-min test interval but differed significantly at the 30- and 60-min test intervals. Whereas sham slices showed stable potentiation for the entire 60-min assessment period, slices in all of the injury groups exhibited a significant decline in potentiation over this period. These experiments reveal a previously unknown effect of TBI whereby experimentally induced injury results in a chronic inability of the CA1 hippocampus to maintain synaptic plasticity. They also provide evidence that sham surgical procedures can significantly influence hippocampal physiology at the acute post-TBI intervals. The results have implications for the mechanisms underlying the impaired synaptic plasticity following TBI.

Animals↗
PubMed1995

Development of excitatory and inhibitory postsynaptic potentials in the rat neocortex.

The postnatal development of synaptic potentials in the rat neocortex is characterized by the sequential appearance of functional excitatory and inhibitory synapses. Morphological and electrophysiological studies provided evidence that at early stages of development, pyramidal cells are extensively coupled to each other, presumably via gap junctions. Thus, immature neurons are able to communicate through pathways that are not available or only weakly expressed in the mature neocortex. During the very early postnatal period, excitatory synaptic inputs prevail. Excitatory postsynaptic potentials (EPSPs) are characteristically long in duration and show high sensitivity to frequent stimulation. Although spontaneous inhibitory postsynaptic potentials (IPSPs) and mature responses to exogenously applied gamma-aminobutyric acid (GABA) have been described during the first postnatal week, evoked IPSPs do not develop before postnatal day 10 (P10). During the period of maximum synaptogenesis (P11 to P20), GABA-mediated synaptic inhibition develops and pyramidal cells respond to afferent activation with efficient EPSPs and IPSPs. These postsynaptic potentials gradually mature during the late postnatal period. The delayed development of synaptic inhibition in the neocortex simultaneously promotes synaptic plasticity while increasing seizure susceptibility. On the one hand, the functional lack of synaptic inhibition during early stages of development enables a period of enhanced neuronal activity and augmented synaptic plasticity necessary to form proper synaptic connections. On the other hand, the absence of inhibitory control over excitatory processes increases the vulnerability of the developing neocortex to seizure activity during postnatal ontogenesis.

Aging↗
PubMed2000

Regulation of AMPA receptors by phosphorylation.

The AMPA receptors for glutamate are oligomeric structures that mediate fast excitatory responses in the central nervous system. Phosphorylation of AMPA receptors is an important mechanism for short-term modulation of their function, and is thought to play an important role in synaptic plasticity in different brain regions. Recent studies have shown that phosphorylation of AMPA receptors by cAMP-dependent protein kinase (PKA) and Ca2+- and calmodulin-dependent protein kinase II (CaMKII) potentiates their activity, but phosphorylation of the receptor subunits may also affect their interaction with intracellular proteins, and their expression at the plasma membrane. Phosphorylation of AMPA receptor subunits has also been investigated in relation to processes of synaptic plasticity. This review focuses on recent advances in understanding the molecular mechanisms of regulation of AMPA receptors, and their implications in synaptic plasticity.

Animals↗
PubMedDate not supplied

[Mechanisms of modification of excitatory and inhibitory inputs in various neurons of olivary-cerebellar network].

It is known from the experimental data that at different cerebellar neurons there are voltage-dependent Ca2+ channels, NMDA receptors, metabotropic glutamate and GABAB receptors. This receptor arrangement ensures that activation of excitatory and inhibitory input results in changes in activity of protein kinases and phosphatases and subsequent modification of synaptic efficacy. The mechanism of synaptic plasticity is advanced that in accordance with the known experimental data concerning the modification of excitatory and inhibitory inputs to Purkinje cells, granule cells, and deep cerebellar nuclei cells. The mechanism is based on a postulate that phosphorylation/dephosphorylation of AMPA (GABAA) receptors on cerebellar cells causes the LTP/LTD of excitatory (LTD/LTP of inhibitory) transmission. It is assumed that modification rules for Purkinje cells, granule cells, and deep cerebellar nuclei cells, wherein cGMP-dependent protein kinase G is involved in synaptic plasticity, are distinct from those of hippocampal/neocortical cells, wherein cAMP-dependent protein kinase A is involved in synaptic plasticity, since cGMP (cAMP) concentration decreases (increases) with Ca2+ rise.

Animals↗