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PubMed2001

Intrinsic stabilization of output rates by spike-based Hebbian learning.

We study analytically a model of long-term synaptic plasticity where synaptic changes are triggered by presynaptic spikes, postsynaptic spikes, and the time differences between presynaptic and postsynaptic spikes. The changes due to correlated input and output spikes are quantified by means of a learning window. We show that plasticity can lead to an intrinsic stabilization of the mean firing rate of the postsynaptic neuron. Subtractive normalization of the synaptic weights (summed over all presynaptic inputs converging on a postsynaptic neuron) follows if, in addition, the mean input rates and the mean input correlations are identical at all synapses. If the integral over the learning window is positive, firing-rate stabilization requires a non-Hebbian component, whereas such a component is not needed if the integral of the learning window is negative. A negative integral corresponds to anti-Hebbian learning in a model with slowly varying firing rates. For spike-based learning, a strict distinction between Hebbian and anti-Hebbian rules is questionable since learning is driven by correlations on the timescale of the learning window. The correlations between presynaptic and postsynaptic firing are evaluated for a piecewise-linear Poisson model and for a noisy spiking neuron model with refractoriness. While a negative integral over the learning window leads to intrinsic rate stabilization, the positive part of the learning window picks up spatial and temporal correlations in the input.

Action Potentials↗
PubMed2005

Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization.

The prefrontal cortex and the hippocampus exhibit converging projections to the nucleus accumbens and have functional reciprocal connections via indirect pathways. As a result, information processing between these structures is likely to be bidirectional. Using evoked potential measures, we examined the interactions of these inputs on synaptic plasticity within the accumbens. Our results show that the direction of information flow between the prefrontal cortex and limbic structures determines the synaptic plasticity that these inputs exhibit within the accumbens. Moreover, this synaptic plasticity at hippocampal and prefrontal inputs selectively involves dopamine D1 and D2 activation or inactivation, respectively. Repeated cocaine administration disrupted this synaptic plasticity at hippocampal and prefrontal cortical inputs and goal-directed behavior in the spatial maze task. Thus, interactions of limbic-prefrontal cortical synaptic plasticity and its dysfunction within the accumbens could underlie complex information processing deficits observed in individuals following psychostimulant administration.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Retrograde signaling at central synapses.

Transcellular retrograde signaling from the postsynaptic target cell to the presynaptic neuron plays critical roles in the formation, maturation, and plasticity of synaptic connections. We here review recent progress in our understanding of the retrograde signaling at developing central synapses. Three forms of potential retrograde signals-membrane-permeant factors, membrane-bound factors, and secreted factors-have been implicated at both developing and mature synapses. Although many of these signals may be active constitutively, retrograde factors produced in association with activity-dependent synaptic plasticity, e.g., long-term potentiation and long-term depression, are of particular interest, because they may induce modification of neuronal excitability and synaptic transmission, functions directly related to the processing and storage of information in the nervous system.

Animals↗
PubMed1996

Development of short-term heterosynaptic facilitation at aplysia sensorimotor synapses in vitro is accompanied by changes in the functional expression of presynaptic serotonin receptors.

1. The sensorimotor synapse of Aplysia expresses various shortlasting changes in synaptic efficacy including homosynaptic depression (HSD) and heterosynaptic facilitation by serotonin (5-HT) either at nondepressed sensory neuron (SN) synaptic connections or at SN synaptic connections first depressed by HSD. We examined the temporal sequence of expression for these three forms of synaptic plasticity as synaptic connections between SN and target motor cell L7 were reestablished and stabilized in cell culture. The same cultures were reexamined at different time points. 2. We found that only HSD and facilitation of nondepressed synapses were expressed at "mature" levels on day 1 in culture, whereas facilitation of depressed connections was significantly weaker on day 1 than the facilitation evoked on day 4. 3. The late expression of 5-HT facilitation of depressed SN synaptic connections was not a result of a reduced capacity of two kinases activated by 5-HT (protein kinase A and protein kinase C) to evoke facilitation. Direct activation of the kinases with either cyclic AMP or phorbol esters evoked the synaptic facilitation both on day 1 and day 4. 4. The late expression of 5-HT facilitation of depressed SN synaptic connections was correlated with the late functional expression of receptors sensitive to 5-HT antagonists cyproheptidine or methiothepin. Both antagonists significantly interfered with 5-HT facilitation on day 4, but both had little effect on 5-HT facilitation of the same cultures examined on day 1. 5. Unlike the properties of SNs in the intact nervous system, both antagonists reduced significantly the excitability changes evoked by 5-HT when the SNs were plated either alone or with target cell L11 that fails to induce synapse formation. When cultured with L7, however, both antagonists evoked little change in 5-HT excitability. In the presence of L7, the SNs expressed the phenotype more typical of SNs in the intact nervous system. 6. The results suggest that target interactions not only influence the formation of chemical connections but they also may regulate the acquisition of specific plastic properties by the presynaptic neuron including the functional expression of receptors for neuromodulators.

Animals↗
PubMed2004

Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins.

Experience-dependent plasticity is thought to involve selective change in pre-existing brain circuits, involving synaptic plasticity. One model for looking at experience-dependent plasticity is environmental enrichment (EE), where animals are exposed to a complex novel environment. Previous studies using electron microscopy showed that EE resulted in synaptic plasticity in the visual cortex and hippocampus. However, the areas in the brain that have been examined following EE have been limited. The present study quantified potential synaptic plasticity throughout the brains of C57BL/6 mice using an enzyme-linked immunosorbent assay (ELISA) for two synaptic proteins, synaptophysin and PSD-95. EE resulted in increased synaptophysin and PSD-95 levels through major brain regions, including anterior and posterior areas of the forebrain, hippocampus, thalamus, and hypothalamus. However, no changes in synaptophysin were detected in the cerebellum. These results demonstrate that EE results in an increase in levels of both pre- and post-synaptic proteins in multiple regions of the brain, and it is possible that such changes represent the underlying synaptic plasticity occurring in EE.

Adaptation, Physiological↗
PubMed2003

Group I mGlu receptors regulate the expression of the neuronal calcium sensor protein VILIP-1 in vitro and in vivo: implications for mGlu receptor-dependent hippocampal plasticity?

Metabotropic glutamate (mGlu) receptors are involved in several forms of synaptic plasticity in the rat hippocampus. Agonists which activate group I mGlu receptors induce slow-onset potentiation without prior tetanization in the hippocampal area CA1. Activation of group I mGlu receptors induces protein synthesis which may contribute to mGlu receptor-dependent forms of long-term plasticity. Calcium-binding proteins are widely considered to comprise key elements for synaptic plasticity. Therefore, we investigated whether the calcium sensor protein VILIP-1 is associated with group I mGlu receptor-mediated plasticity in the dentate gyrus (DG) in vivo.Application of either the group I and II mGlu agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) or the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) resulted in slow-onset potentiation in the DG of adult rats. In hippocampal cell cultures both agonists elicited an enhanced expression of VILIP-1. In situ hybridization revealed strong hippocampal expression of VILIP-1 and intracerebral application of DHPG to adult rats significantly enhanced hippocampal VILIP-1 expression. The DHPG effects in both, hippocampal cultures and in vivo, were prevented by the group I mGlu receptor antagonist 4-Carboxyphenylglycine (4CPG). Calcium sensor proteins thus appear to be regulated by mGlu receptors in an activity-dependent manner. A specific role for group I mGlu receptors is evident. Furthermore, the sensor proteins may function as molecular switches for the long-term regulation of synaptic plasticity.

Animals↗
PubMedDate not supplied

A genetic switch for long-term memory.

Current models of brain function hold that learning corresponds to changes in the efficacy of single synapses. The study of learning and of a variety of forms of synaptic plasticity has revealed that both have at least two phases: an early phase that is not dependent on protein synthesis and a late phase that depends on new transcription and translation. Our laboratory has examined synaptic plasticity in Aplysia and in mice to better understand the regulatory events that lead to the induction of the late, protein synthesis-dependent phase of synaptic plasticity. Our recent studies of Aplysia have revealed that the genes that control the late phase of synaptic facilitation are controlled by both an activator, ApCREB1, and a repressor, ApCREB2. This leads to a model in which the late phase of synaptic facilitation is initiated by a perturbation of the balance between activators and repressors of transcription; this perturbation can be accomplished by regulating the activator, the repressor, or both. We, and others, have shown that this transcriptional switch is conserved, at least in part, in the regulation of synaptic plasticity in mice: CREB is implicated in activation of genes required for LTP, a model for synaptic plasticity in the mammalian hippocampus. We speculate that a similar balance between activators and repressors may regulate the genes required for long-term memory in mammals.

Animals↗
PubMed2002

In vitro conditioning induces morphological changes in Hermissenda type B photoreceptor.

Short- and long-term synaptic plasticity are considered to be cellular substrates of learning and memory. The mechanisms underlying synaptic plasticity especially with respect to morphology, however, are not known. In vitro conditioning in molluscan preparations is a well established form of short-term synaptic plasticity. Five paired presentations of light and vestibular stimulation to the isolated nervous system of Hermissenda results in an increase in excitability of the identified neuron, the type B photoreceptor, indicated by 2 measures, an increase in the input resistance and a cumulative depolarization after the cessation of light stimulus recorded from the cell soma. The terminal branches of type B photoreceptors iontophoretically injected with fluorescent dye were analyzed using computer-aided 3-dimensional reconstruction of images obtained using a confocal microscope under 'blind' conditions. The terminal branches contracted along the centro-lateral axis within an hour after conditioning, paralleling the increase in neuronal excitability. These data suggest that in vitro conditioning in Hermissenda is a form of short-term synaptic plasticity that involves changes in macromolecular synthesis.

Animals↗
PubMed2006

Dopamine D1/D5 receptors gate the acquisition of novel information through hippocampal long-term potentiation and long-term depression.

Hebbian learning models require that neurons are able to both strengthen and weaken their synaptic connections. Hippocampal synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), has been implicated in both spatial memory formation as well as novelty acquisition. In addition, the ventral tegmental area-hippocampal loop has been proposed to control the entry of information into long-term memory, whereas the dopaminergic system is believed to play an important role in information acquisition and synaptic plasticity. D1/D5 dopamine receptors are positively coupled to adenylyl cyclase and have been to modulate certain forms of synaptic plasticity, particularly in vitro. We investigated how D1/D5 dopamine receptors modify long-lasting synaptic plasticity at CA1 synapses of adult freely moving rats and found that receptor activation lowered the threshold for the induction of both LTP and LTD. Specific types of learning are associated with specific types of hippocampal synaptic plasticity. We found that object-configuration learning, facilitation of late-phase LTD by object exploration, and late-phase LTP by exploration of empty space were all prevented by D1/D5 receptor antagonism. Furthermore, receptor antagonism prevented electrically induced late-LTP, whereas receptor activation facilitated induction of both LTP and LTD by patterned electrical stimulation. These findings suggest that the dopaminergic system, acting via D1/D5 receptors, gates long-term changes in synaptic strength and that these changes are a critical factor in the acquisition of novel information.

Animals↗
PubMed2001

An experimental test of the role of postsynaptic calcium levels in determining synaptic strength using perirhinal cortex of rat.

1. We have investigated the prediction of a relationship between the magnitude of activity-dependent increases in postsynaptic calcium and both the magnitude and direction of synaptic plastic change in the central nervous system. 2. Activity-dependent increases in calcium were buffered to differing degrees using a range of concentrations of EGTA and the effects on synaptic plasticity were assessed. Activity-dependent synaptic plasticity was induced during whole-cell recording in rat perirhinal cortex in vitro. In control conditions (0.5 mM EGTA) low frequency stimulation (LFS; 200 stimuli) delivered to neurones held at -40 or -70 mV induced long-term depression (LTD) or, at -10 mV, induced long-term potentiation (LTP). 3. The relationship between EGTA concentration (0.2 to 10 mM) and the magnitude of LTD was examined. This relationship described a U-shaped curve, as predicted by models of synaptic plasticity. This provides strong evidence that the magnitude of LTD is determined by the magnitude of the increase in intracellular calcium concentration. 4. LFS paired with depolarisation to -10 mV induced LTD, no change or LTP as activity-dependent postsynaptic calcium levels were allowed to increase progressively by the use of progressively lower concentrations of buffer (10 to 0.2 mM EGTA). 5. We investigated if the lack of plasticity that occurs at the transition between LTD and LTP is due to induction of both of these processes with zero net change, or is due to neither LTD nor LTP being induced. These experiments were possible as LTP but not LTD was blocked by the protein kinase inhibitor staurosporine while LTD but not LTP was blocked by the mGlu receptor antagonist MCPG. At the transition between LTD and LTP, blocking LTP mechanisms did not uncover LTD whilst blocking LTD mechanisms did not uncover LTP. This suggests that the transition between LTD and LTP is due to the lack of induction of both of these processes and also suggests that these two processes are induced independently of one another.

Animals↗
PubMed2004

[A role for microtubules in mental diseases?].

Microtubules are key cytoskeletal components in the cytoplasm of eukaryotic cells where they have pleiotropic and vital roles in functions such as cell division, trafficking or morphogenesis. Microtubules are especially abundant in neurons. Although microtubules are in many cells dynamic polymers, they exhibit an extreme state of stability in neurons. Previous work has indicated a central role of microtubule associated proteins called STOPs in neuronal microtubule stabilization. We have recently developed STOP null mice. These mice were devoid of stable brain microtubules but to our surprise had nevertheless an apparently normal brain anatomy. However the mice showed synaptic defects affecting different forms of long- and short-term synaptic plasticity. These synaptic defects were associated with severe behavioral defects that showed a remarkable sensitivity to long-term treatment with neuroleptics. We discuss the relationship of the phenotypes observed in STOP null mice with current models of schizophrenia in which the multiple, severe, and neuroleptic sensitive mental disorders caused by the disease are due to a "disease of the synapse".

Animals↗
PubMed2004

Long-term potentiation and memory.

One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.

Animals↗
PubMed2006

Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia.

In recent years, it has been proposed that synaptic dysfunction may be an important etiological factor for Alzheimer's disease (AD). This hypothesis has important implications for the analysis of AD genetic risk in case-control studies. In the present work, we analyzed common functional polymorphisms in three synaptic plasticity-related genes (brain-derived neurotrophic factor, BDNF Val66Met; catechol-O-methyl transferase, COMT Val158; ubiquitin carboxyl-terminal hydroxylase, UCHL1 S18Y) in a sample of 102 AD cases and 168 age and sex matched controls living in Bogotá, Colombia. There was not association between UCHL1 polymorphism and AD in our sample. We have found an initial association with BDNF polymorphism in familial cases and with COMT polymorphism in male and sporadic patients. These initial associations were lost after Bonferroni correction for multiple testing. Unadjusted results may be compatible with the expected functional effect of variations in these genes on pathological memory and cognitive dysfunction, as has been implicated in animal and cell models and also from neuropsychological analysis of normal subjects carriers of the AD associated genotypes. An exploration of functional variants in these and in other synaptic plasticity-related genes (a synaptogenomics approach) in independent larger samples will be important to discover new genes associated with AD.

Aged↗
PubMed2006

REM sleep deprivation attenuates actin-binding protein cortactin: a link between sleep and hippocampal plasticity.

Rapid eye-movement sleep (REMS) is thought to affect synaptic plasticity. Cortactin is a cytoskeletal protein critically involved in the regulation of actin branching and stabilization including the actin backbone of dendritic spines. Hippocampal cortactin levels, phosphorylation, and processing appear to be altered during learning and long-term potentiation (LTP); consistent with a role for cortactin in the dendritic restructuring that accompanies synaptic plasticity. In this study juvenile male Sprague-Dawley rats were selectively REMS-deprived (RD) for 48 h by the flowerpot method. Cage control (CC) and large pedestal control (PC) animals were used for comparison. Animals were euthanized immediately, or 12 h, after removal from the pedestal. The hippocampus was dissected, flash-frozen, and stored for subsequent Western blot or quantitative RT-PCR analysis of cortactin. Cortactin mRNA/cDNA levels initially rose in PC and RD rats but returned to CC levels by 12 h after removal from the pedestal. Predictably cortactin protein levels were initially unchanged but were up-regulated after 12 h. The PC group had more total and tyrosine-phosphorylated cortactin protein expression than the RD and CC groups. This increase in cortactin was likely due to the exposure of the rats to the novel environment of the deprivation chambers thus triggering plasticity events. The lack of REMS, however, severely hampered cortactin protein up-regulation and phosphorylation observed in the PC group suggesting an attenuation of plasticity-related events. Thus, these data support a functional link between REMS and cytoskeletal reorganization in the hippocampus, a process that is essential for synaptic plasticity.

Actins↗
PubMed1998

Primed facilitation of homosynaptic long-term depression and depotentiation in rat hippocampus.

Previous studies have demonstrated that prior synaptic activity can influence the subsequent induction of synaptic plasticity in the brain. Such temporal modulation of synaptic plasticity has been called "metaplasticity." In this report, we describe the facilitatory effects of high-frequency stimulation on the induction of homosynaptic long-term depression (LTD) in the CA1 region of the rat hippocampus. The LTD induced by low-frequency stimulation (1 Hz) protocols was found to be homosynaptic and NMDA receptor-dependent. The facilitatory effects of the high-frequency stimulation-induced priming event itself were found to be NMDA receptor-independent and to have a duration of at least 90 min. The effects of priming also were heterosynaptic, because the induction of synaptic plasticity by low-frequency stimulation was enhanced at an unprimed synaptic pathway after the priming of an independent pathway. In addition to enhancing LTD, priming also enhanced the reversal of long-term potentiation elicited by a 5 Hz depotentiation protocol. Our results provide examples of how metaplasticity may play a key role in the ongoing modulation of the induction and stabilization of alterations in synaptic strength.

2-Amino-5-phosphonovalerate↗
PubMed2005

Late postnatal maturation of excitatory synaptic transmission permits adult-like expression of hippocampal-dependent behaviors.

Sensorimotor systems in altricial animals mature incrementally during early postnatal development, with complex cognitive abilities developing late. Of prominence are cognitive processes that depend on an intact hippocampus, such as contextual-configural learning, allocentric and idiocentric navigation, and certain forms of trace conditioning. The mechanisms that regulate the delayed maturation of the hippocampus are not well understood. However, there is support for the idea that these behaviors come "on line" with the final maturation of excitatory synaptic transmission. First, by providing a timeline for the first behavioral expression of various forms of learning and memory, this study illustrates the late maturation of hippocampal-dependent cognitive abilities. Then, functional development of the hippocampus is reviewed to establish the temporal relationship between maturation of excitatory synaptic transmission and the behavioral evidence of adult-like hippocampal processing. These data suggest that, in rats, mechanisms necessary for the expression of adult-like synaptic plasticity become available at around 2 postnatal weeks of age. However, presynaptic plasticity mechanisms, likely necessary for refinement of the hippocampal network, predominate and impede information processing until the third postnatal week.

Animals↗
PubMed2006

Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation.

The myristoylated alanine-rich C kinase substrate (MARCKS) is a primary protein kinase C (PKC) substrate in brain thought to transduce PKC signaling into alterations in the filamentous (F) actin cytoskeleton. Within the adult hippocampus, MARCKS is highly expressed in the dentate gyrus (DG)-CA3 mossy fiber pathway, but is expressed at low levels in the CA3-CA1 Schaffer collateral-CA1 pathway. We have previously demonstrated that 50% reductions in MARCKS expression in heterozygous Marcks mutant mice produce robust deficits in spatial reversal learning, but not contextual fear conditioning, suggesting that only specific aspects of hippocampal function are impaired by reduction in MARCKS expression. To further elucidate the role of MARCKS in hippocampal synaptic plasticity, in the present study we examined basal synaptic transmission, paired-pulse facilitation, post-tetanic potentiation, and long-term potentiation (LTP) in the hippocampal mossy fiber-CA3 and Schaffer collateral-CA1 pathways of heterozygous Marcks mutant and wild-type mice. We found that LTP is significantly impaired in the mossy fiber-CA3 pathway, but not in the Schaffer collateral-CA1 pathway, in heterozygous Marcks mutant mice, whereas basal synaptic transmission, paired-pulse facilitation, and post-tetanic potentiation are unaffected in both pathways. These findings indicate that a 50% reduction in MARCKS expression impairs processes required for long-term, but not short-term, synaptic plasticity in the mossy fiber-CA3 pathway. The implications of these findings for the role of the mossy fiber-CA3 pathway in hippocampus-dependent learning processes are discussed.

Animals↗
PubMed1977

Storing covariance with nonlinearly interacting neurons.

A time-dependent, nonlinear model of neuronal interaction which was probabilistically analyzed in a previous article is shown here to be a natural generalization of the Hartline-Ratliff model of the Limulus retina. Although the primary physical variables in the model are the membrane potentials of neurons, the equations which govern the means and covariances of the membrane potentials are coupled through the average firing rates; as a consequence, the average firing rates control the selective storage and retrieval of covariance information. Motor learning in the cerebellar cortex is treated as a problem of covariance storage, and a predicition is made for the underlying synaptic plasticity: the change in synaptic strength between a parallel fiber and a Purkinje cell should be proportional to the covariance between discharges in the parallel fiber and the climbing fiber. Unlike previous proposals for synaptic plasticity, this prediction requires both facilitation and depression to occur (under different conditions) at the same synapse.

Cerebellum↗