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PubMed1997

Insensitivity of the hippocampus to environmental stimulation during postnatal development.

Development of cortical sensory systems is influenced by environmental experience during "sensitive periods," before onset of behavioral function. During these periods, synaptic plasticity is observed, and neuronal function shows increased responsiveness to environmental stimulation. Because the hippocampus is late to develop, and because it demonstrates synaptic plasticity before the onset of behavioral function, this experiment was designed to determine whether, like the sensory cortices, the hippocampus undergoes a period of enhanced responsiveness to the environment. Rats at three ages [postnatal day 16 (P16), P23, and P30] were tested on a hippocampally dependent task, spontaneous alternation, and exposed to a novel environment. They were then killed and processed for immunocytochemistry to Fos or for in vitro electrophysiology in hippocampal area CA1. Age-matched control subjects were killed immediately after removal from the home cage. Spontaneous alternation was only observed in the oldest (P30) animals. In these same animals, the environmental manipulation resulted in an increase in Fos-like immunoreactivity (FL-IR), relative to controls, and a decrease in the ability to induce long-term potentiation (LTP). In P16 and P23 animals, the environmental manipulation resulted in no differences in hippocampal FL-IR or LTP. These results suggest that, rather than showing increased responsiveness to the environment at these ages, the hippocampus is environmentally insensitive and that it is isolated from the effects of environmental stimuli. The hippocampus, a neural region important for higher cognitive function, may develop via a mechanism different from those observed in the primary sensory cortices.

Aging↗

PubMed2002

Rapid regrowth of hippocampal mossy fibres and preceding maturation of NMDA receptor-mediated neurotransmission.

Early in postnatal development, glutamatergic synapses contain primarily NMDA receptors and progressively acquire AMPA receptor function. To determine whether this transformation occurs in a process of regenerative synaptogenesis following axotomy, we investigated the recovery of AMPA and NMDA receptor-mediated neurotransmission after the transection of mossy fibres (MF) in organotypic hippocampal cultures. An NMDA component could already be elicited 1 day after the lesion and reached a saturated level after 3 days. Thereafter, an AMPA component appeared and slowly matured after 10 days. The preceding establishment of NMDA receptor function implies that immature MF synapses are functionally silent at least for the first several days of recovery. The appearance of AMPA receptor-mediated neurotransmission was unchanged in the presence of an NMDA-receptor antagonist or tetrodotoxin, which suggests that the AMPA receptor maturation is virtually independent of neuronal activity. Thus, the conversion of silent to functional synapses is not unique to synaptic plasticity or developmental processes but also occurs in recovery after brain damage, but its mechanism is likely to differ from NMDA receptor-dependent recruitment of AMPA receptors in synaptic plasticity.

2-Amino-5-phosphonovalerate↗

PubMed2003

In vivo insular cortex LTP induced by brain-derived neurotrophic factor.

Recent studies suggest that brain-derived neurotrophic factor (BDNF) plays a critical role in long-term synaptic plasticity in the adult brain. Previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of different aversive learning tasks, have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induces an N-methyl-D-aspartate (NMDA)-dependent form of long-term potentiation (LTP) in the IC of adult rats in vivo. Here, we show that acute intracortical microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the Bla-IC projection of anesthetized adult rats. This constitutes an in vivo demonstration of neurotrophin-induced potentiation of synaptic transmission in the neocortex. These findings support the concept that BDNF could be a synaptic messenger involved in activity-dependent synaptic plasticity.

Animals↗

PubMed2004

Synaptic computation.

Neurons are often considered to be the computational engines of the brain, with synapses acting solely as conveyers of information. But the diverse types of synaptic plasticity and the range of timescales over which they operate suggest that synapses have a more active role in information processing. Long-term changes in the transmission properties of synapses provide a physiological substrate for learning and memory, whereas short-term changes support a variety of computations. By expressing several forms of synaptic plasticity, a single neuron can convey an array of different signals to the neural circuit in which it operates.

Animals↗

PubMed1999

Pathophysiological implications of the structural organization of the excitatory synapse.

The glutamatergic synapse is the key structure in the development of activity-dependent synaptic plasticity in the central nervous system. The analysis of the complex biochemical mechanisms at the basis of the long-term changes in synaptic efficacy have received a tremendous impulse by the observation that the post-synaptic constituents of the synapse can be separated and purified through a simple procedure involving detergent treatment of synaptosomes and differential centrifugation. In this fraction, called post-synaptic density (PSD), the functional interactions of its constituents are preserved. The various subunits of ionotropic glutamate receptors are held in register with the presynaptic active zone through their interaction with linker proteins. N-methyl-D-aspartate (NMDA) subunits NR2A and NR2B, bind to the PSD protein called PSD-95, which in turn binds neuroligins, providing a handle for interacting with neurexin, located in the plasma membrane at the presynaptic active zone. Additional clustering of NMDA receptors is provided through the binding of NRI subunits to the cytoskeletal protein alpha-actinin-2. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors are other important constituents of PSDs and bind to different anchoring proteins. Phosphorylation processes have long been known to modulate NMDA receptor functional activity: the finding that several protein kinases, particularly Ca2+/Calmodulin-dependent protein kinase II and protein tyrosine kinases of the src family, are major constituents of PSDs has allowed to demonstrate that these enzymes are localized in a strategic position of the glutamatergic synapse, so that their activation provides a means for NMDA receptor function regulation upon its activation. The relevance of these mechanisms has been demonstrated in experimental models of pathologies involving deficits in synaptic plasticity, such as in streptozotocin-induced diabetes and in an animal model of prenatal induced ablation of hippocampal neurons. Both animal models display disturbances in long-term potentiation and cognitive deficits, thus providing in vivo models to study pathology related changes in both the structure and the function of the excitatory synapse.

Alkylating Agents↗

PubMed1994

Non-Hebbian properties of long-term potentiation enable high-capacity encoding of temporal sequences.

A hypothesis commonly found in biological and computational studies of synaptic plasticity embodies a version of the 1949 postulate of Hebb that coactivity of pre- and postsynaptic elements results in increased efficacy of their synaptic contacts. This general proposal presaged the identification of the first and still only known long-lasting synaptic plasticity mechanism, long-term potentiation (LTP). Yet the detailed physiology of LTP induction and expression differs in many specifics from Hebb's rule. Incorporation of these physiological LTP constraints into a simple non-Hebbian network model enabled development of "sequence detectors" that respond preferentially to the sequences on which they were trained. The network was found to have unexpected capacity (e.g., 50 x 10(6) random sequences in a network of 10(5) cells), which scales linearly with network size, thereby addressing the question of memory capacity in brain circuitry of realistic size.

Algorithms↗

PubMed2005

Supervised learning through neuronal response modulation.

Neural networks that are trained to perform specific tasks must be developed through a supervised learning procedure. This normally takes the form of direct supervision of synaptic plasticity. We explore the idea that supervision takes place instead through the modulation of neuronal excitability. Such supervision can be done using conventional synaptic feedback pathways rather than requiring the hypothetical actions of unknown modulatory agents. During task learning, supervised response modulation guides Hebbian synaptic plasticity indirectly by establishing appropriate patterns of correlated network activity. This results in robust learning of function approximation tasks evenwhenmultiple output units representing different functions share large amounts of common input. Reward-based supervision is also studied, and a number of potential advantages of neuronal response modulation are identified.

Feedback↗

PubMed2005

A single day of ethanol exposure during development has persistent effects on bi-directional plasticity, N-methyl-D-aspartate receptor function and ethanol sensitivity.

To determine factors that contribute to the learning deficits observed in individuals with fetal alcohol syndrome, we examined the effects of early postnatal ethanol exposure on forms of synaptic plasticity thought to underlie memory. Treatment of rat pups with ethanol on postnatal day 7 impaired the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation and abolished homosynaptic long-term depression in the CA1 region of hippocampal slices prepared at postnatal day 30. An N-methyl-D-aspartate receptor-independent form of long-term potentiation induced by very high frequency stimulation could be induced in slices from ethanol-treated rats. Defects in long-term depression correlated with a diminished contribution of ifenprodil-sensitive N-methyl-D-aspartate receptors to synaptic transmission and defects in a spontaneous alternation behavioral task. Rats exposed to ethanol on postnatal day 7 also exhibited diminished sensitivity of synaptic N-methyl-D-aspartate receptors to block by ethanol at postnatal day 30 and decreased behavioral sedation to systemic ethanol injections. These results indicate that changes in synaptic plasticity and N-methyl-D-aspartate receptor function are likely to provide a neural substrate for the cognitive and behavioral changes that follow developmental ethanol exposure.

Animals↗

PubMed2006

Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory.

Raf kinases are downstream effectors of Ras and upstream activators of the MEK-ERK cascade. Ras and MEK-ERK signaling play roles in learning and memory (L&M) and neural plasticity, but the roles of Raf kinases in L&M and plasticity are unclear. Among Raf isoforms, B-raf is preferentially expressed in the brain. To determine whether B-raf has a role in synaptic plasticity and L&M, we used the Cre-LoxP gene targeting system to derive forebrain excitatory neuron B-raf knockout mice. This conditional knockout resulted in deficits in ERK activation and hippocampal long-term potentiation (LTP) and impairments in hippocampus-dependent L&M, including spatial learning and contextual discrimination. Despite the widespread expression of B-raf, this mutation did not disrupt other forms of L&M, such as cued fear conditioning and conditioned taste aversion. Our findings demonstrate that B-raf plays a role in hippocampal ERK activation, synaptic plasticity, and L&M.

Animals↗

PubMed1999

Roles of postsynaptic density-95/synapse-associated protein 90 and its interacting proteins in the organization of synapses.

Synapses are central stages for neurotransmission. Neurotransmitters are released from the presynaptic membrane of one neuron, and bind to the receptors accumulated at the postsynaptic membrane, followed by the activation of the other neuron. The strength of a synapse is modified depending on the history of the previous neurotransmissions. This property is called synaptic plasticity and is implicated in learning and memory. Synapses contain not only the components essential for neurotransmission but also the signalling molecules involved in synaptic plasticity. The elucidation of the molecular structures of synapses is one of the key steps to understand the mechanism of learning and memory. Recent studies have revealed postsynaptic density (PSD)-95/synapse-associated protein (SAP) 90 as a core component in the architecture of synapses. In this review, we summarize up-to-date information about PSD-95/SAP90 and its interacting proteins, and the organization of synapses orchestrated

Animals↗

PubMed1993

Emotional memory systems in the brain.

The neural mechanisms of emotion and memory have long been thought to reside side by side, if not in overlapping structures, of the limbic system. However, the limbic system concept is no longer acceptable as an account of the neural basis of memory or emotion and is being replaced with specific circuit accounts of specific emotional and memory processes. Emotional memory, a special category of memory involving the implicit (probably unconscious) learning and storage of information about the emotional significance of events, is modeled in rodent experiments using aversive classical conditioning techniques. The neural system underlying emotional memory critically involves the amygdala and structures with which it is connected. Afferent inputs from sensory processing areas of the thalamus and cortex mediate emotional learning in situations involving specific sensory cues, whereas learning about the emotional significance of more general, contextual cues involves projections to the amygdala from the hippocampal formation. Within the amygdala, the lateral nucleus (AL) is the sensory interface and the central nucleus the linkage with motor systems involved in the control of species-typical emotional behaviors and autonomic responses. Studies of cellular mechanisms in these pathways have focused on the direct relay to the lateral amygdala from the auditory thalamus. These studies show that single cells in AL respond to both conditioned stimulus and unconditioned stimulus inputs, leading to the notion that AL might be a critical site of sensory-sensory integration in emotional learning. The thalamo-amygdala pathway also exhibits long-term potentiation, a form of synaptic plasticity that might underlie the emotional learning functions of the circuit. The thalamo-amygdala pathway contains and uses the amino acid glutamate in synaptic transmission, suggesting the possibility that an amino-acid mediated form of synaptic plasticity is involved in the emotional learning functions of the pathway. We are thus well on the way to a systems level and a cellular understanding of at least one form of emotional learning and memory.

Animals↗

PubMed2000

Localization of a short-term memory in Drosophila.

Memories are thought to be due to lasting synaptic modifications in the brain. The search for memory traces has relied predominantly on determining regions that are necessary for the process. However, a more informative approach is to define the smallest sufficient set of brain structures. The rutabaga adenylyl cyclase, an enzyme that is ubiquitously expressed in the Drosophila brain and that mediates synaptic plasticity, is needed exclusively in the Kenyon cells of the mushroom bodies for a component of olfactory short-term memory. This demonstrates that synaptic plasticity in a small brain region can be sufficient for memory formation.

Adenylyl Cyclases↗

PubMed2004

Two intra-amygdaloid pathways to the central amygdala exhibit different mechanisms of long-term potentiation.

Synaptic plasticity in the amygdala is thought to underlie aversive or rewarding learning and emotional memories. In this study, different mechanisms were found to underlie synaptic plasticity in lateral (LA) and basolateral (BLA) amygdala pathways to the primary output nucleus of the amygdala, the central amygdala (CeA). Specifically, 1) long-term potentiation (LTP) at the BLA-CeA synapses was independent of inhibition and mediated through N-methyl-d-aspartate receptors (NMDARs) and L-type voltage-gated calcium channels (VGCCs), and 2) LTP in the LA-CeA pathway was gated by inhibition and mediated through VGCCs but not NMDARs.

Amygdala↗

PubMed1993

[3H]phorbol ester binding sites and neuronal plasticity in the hippocampus following entorhinal cortex lesions.

Entorhinal cortex lesioning (ECL) produces a loss of more than 80% of the synapses in the outer molecular layer of the hippocampus. However, the loss of synapses is transient. Beginning a few days after denervation, new synapses are formed, virtually replacing the lost inputs within 2 months. Synaptic remodelling induced by ECL is associated with specific modifications of neurotransmitters, hormones and growth factors. Particularly, protein kinase C (PKC) plays important functional roles in receptor-mediated transmembrane signal transduction. PKC is also involved in various aspects of synaptic plasticity, such as cellular growth and differentiation. To investigate further the potential roles of PKC in synaptic plasticity observed in the ECL model, [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, a putative marker of PKC, was examined at different times post-lesion. [3H]PDBu binding sites transiently decreased bilaterally at 2 and 8 days post-lesion (20%) in different laminae and sub-fields of the rostral hippocampus but returned to control values at 14 and 30 days post-lesion. In caudal portion of the hippocampus, [3H]PDBu binding was also decreased at 2 days post-lesion but only on the contralateral side. Interestingly, [3H]PDBu binding sites in the cortex increased by up to 30% in the contralateral side while no significant change was observed in the ipsilateral side at any time post-lesion. It is known that PKC can be regulated by different systems following alterations of neuronal and glial activity. We suggest that these could be involved in the response of PKC and [3H]PDBu binding sites following ECL. Moreover, PKC seemed to be modified in different brain areas in neuronal inputs from the entorhinal cortex and the subsequent reinnervation process.

Acetylcholinesterase↗

PubMed2005

Differential translation and fragile X syndrome.

Fragile X syndrome (FXS) is caused by the transcriptional silencing of the Fmr1 gene, which encodes a protein (FMRP) that can act as a translational suppressor in dendrites, and is characterized by a preponderance of abnormally long, thin and tortuous dendritic spines. According to a current theory of FXS, the loss of FMRP expression leads to an exaggeration of translation responses linked to group I metabotropic glutamate receptors. Such responses are involved in the consolidation of a form of long-term depression that is enhanced in Fmr1 knockout mice and in the elongation of dendritic spines, resembling synaptic phenotypes over-represented in fragile X brain. These observations place fragile X research at the heart of a long-standing issue in neuroscience. The consolidation of memory, and several distinct forms of synaptic plasticity considered to be substrates of memory, requires mRNA translation and is associated with changes in spine morphology. A recent convergence of research on FXS and on the involvement of translation in various forms of synaptic plasticity has been very informative on this issue and on mechanisms underlying FXS. Evidence suggests a general relationship in which the receptors that induce distinct forms of efficacy change differentially regulate translation to produce unique spine shapes involved in their consolidation. We discuss several potential mechanisms for differential translation and the notion that FXS represents an exaggeration of one 'channel' in a set of translation-dependent consolidation responses.

Animals↗

PubMed2000

Receptor blockade reveals a correspondence between hippocampal-dependent behavior and experience-dependent synaptic enhancement.

This study examined the involvement of N-methyl-D-aspartate receptors (NMDARs) in experience-dependent synaptic plasticity. Rats chronically received an NMDA receptor antagonist (AP5) or saline (SAL) and were exposed to individual cages (IC) or environmental enrichment (EC). AP5 impaired measures of hippocampal-dependent behavior and increased locomotor activity. Perforant path synaptic strength, measured in the in vitro hippocampal slice, was increased and long-term potentiation (LTP) was decreased for EC+SAL animals. The experience-dependent effects on synaptic function were inhibited by drug treatment. Measures of synaptic strength were correlated with hippocampal-dependent behavior and synaptic plasticity for EC animals. The results suggest a relationship between hippocampal-dependent behavior and experience-dependent modification of perforant path synaptic function through NMDAR activation.

2-Amino-5-phosphonovalerate↗

PubMed2006

Transcriptional profiling of brain-derived-neurotrophic factor-induced neuronal plasticity: a novel role for nociceptin in hippocampal neurite outgrowth.

Brain derived neurotrophic factor (BDNF) exhibits a sequence of actions on neurons ranging from acute enhancement of transmission to long-term promotion of neurite outgrowth and synaptogenesis associated with learning and memory. The manifold effects of BDNF on neuronal modifications may be mediated by genomic alterations. We previously found that BDNF treatment acutely increases transcription of the synaptic vesicle protein Rab3A, required for trophin-induced synaptic plasticity, as well as the peptide VGF, which increases during learning. To elucidate comprehensive transcriptional programs associated with short- and long-term BDNF exposure, we now examine mRNA abundance and complexity using Affymetrix GeneChips in cultured hippocampal neurons. Consistent with the modulation of synaptic plasticity, BDNF treatment (3-6 h) induced mRNAs encoding the synapse-associated proteins synaptojanin 2, neuronal pentraxin 1, septin 9, and ryanodine receptor 2. BDNF also induced expression of mRNAs encoding neuropeptides (6-12 h), including prepronociceptin, neuropeptide Y, and secretogranin. To determine whether these neuropeptides induced by BDNF mediate neuronal development, we examined their effects on hippocampal neurons. The four mature peptides derived from post-translational processing of the ppNociceptin propeptide induced the expression of several immediate early genes in hippocampal cultures, indicating neuronal activation. To examine the significance of activation, the effects of nociceptin (orphanin FQ) and nocistatin on neurite outgrowth were examined. Quantitative morphometric analysis revealed that nociceptin significantly increased both average neurite length and average number of neurites per neuron, while nocistatin had no effect on these parameters. These results reveal a novel role for nociceptin and suggest that these neuropeptide systems may contribute to the regulation of neuronal function by BDNF.

Animals↗

PubMed2007

TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex.

BACKGROUND: Understanding of the molecular mechanisms of prefrontal cortex (PFC) plasticity is important for developing new treatment strategies for mental disorders such as depression and schizophrenia. Long-term potentiation (LTP) is a valid model for synaptic plasticity. The extracellular proteolytic system composed of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) has recently been shown to play major role in the hippocampal plasticity. METHODS: We tested whether induction of hippocampal-prefrontal LTP results in accumulation of tissue inhibitor of MMP-1, TIMP-1 mRNA, in the PFC of rats and whether adenovirally driven overexpression of TIMP-1 affects LTP. Additional study of slices was done with a specific MMP-9 inhibitor. RESULTS: The TIMP-1 is induced in the rat medial PFC by stimuli evoking late LTP; its overexpression blocks the gelatinolytic activity of the MMP family; its overexpression before tetanization blocks late LTP in vivo; and MMP-9 inhibitor prevents late LTP in vitro. CONCLUSIONS: We suggest a novel extracellular mechanism of late LTP in the PFC, engaging TIMP-1-controlled proteolysis as an element of information integration. Our results may also be meaningful to an understanding of mental diseases and development of new treatment strategies that are based on extracellular mechanisms of synaptic plasticity.

Animals↗