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PubMed2005

Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis.

The matrix metalloproteinase (MMP) enzyme family contributes to the regulation of a variety of brain extracellular matrix molecules. In order to assess their role in synaptic plasticity following traumatic brain injury (TBI), we compared expression of stromelysin-1 (MMP-3) protein and mRNA in two rodent models of TBI exhibiting different levels of recovery: adaptive synaptic plasticity following central fluid percussion injury and maladaptive synaptic plasticity generated by combined TBI and bilateral entorhinal cortical lesion (TBI + BEC). We sampled the hippocampus at 7 days postinjury, targeting a selectively vulnerable brain region and a survival interval exhibiting rapid synaptogenesis. We report elevated expression of hippocampal MMP-3 mRNA and protein after TBI. MMP-3 immunohistochemical staining showed increased protein levels relative to sham-injured controls, primarily localized to cell bodies within the deafferented dendritic laminae. Injury-related differences in MMP-3 protein were also observed. TBI alone elevated MMP-3 immunobinding over the stratum lacunosum moleculare (SLM), inner molecular layer and hilus, while TBI + BEC generated more robust increases in MMP-3 reactivity within the deafferented SLM and dentate molecular layer (DML). Double labeling with GFAP confirmed the presence of MMP-3 within reactive astrocytes induced by each injury model. Semi-quantitative RT-PCR revealed that MMP-3 mRNA also increased after each injury, however, the combined insult induced a much greater elevation than fluid percussion alone: 1.9-fold vs. 79%, respectively. In the TBI + BEC model, MMP-3 up-regulation was spatio-temporally correlated with increased enzyme activity, an effect which was attenuated with the neuroprotective compound MK-801. These results show that distinct pathological conditions elicited by TBI can differentially affect MMP-3 expression during reactive synaptic plasticity. Notably, these effects are both transcriptional and translational and are correlated with functionally active enzyme.

Animals↗
PubMed2005

Rapid eye movement sleep deprivation in post-critical period, adolescent rats alters the balance between inhibitory and excitatory mechanisms in visual cortex.

Suppression of rapid eye movement sleep (REMS) in developing animals has both anatomical and physiological consequences. We have recently shown that initiating REMS deprivation (REMSD) prior to the end of the critical period in young rats delays termination of the critical period (CP) in visual cortex, and, consequently, the synaptic plasticity mechanisms that support a developmentally regulated form of long-term potentiation (LTP) are maintained in an immature state [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431-443]. In CP animals, high-frequency, theta burst stimulation (TBS) directed at the white matter (WM) below visual cortex produces LTP in the post-synaptic cells in layer II/III (LTPWM-III). However, LTPWM-III can be induced in cortical tissue taken from REMS-deprived animals for up to a week beyond the usual end of the CP [J.P. Shaffery, C.M. Sinton, G. Bisset, H.P. Roffwarg, G.A. Marks, Rapid eye movement sleep deprivation modifies expression of long-term potentiation in visual cortex of immature rats, Neuroscience, 110 (2002) 431-443]. Further, in post-CP, adolescent animals (as late as postnatal day 60), REMSD appears to unmask synaptic plasticity mechanisms that allow for production of developmentally regulated LTPWM-III [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. It has been proposed that REMSD's effects on production of LTPWM-III result from a reduction in efficiency of the inhibitory mechanisms thought to precipitate termination of the CP of brain development [J.P. Shaffery, J. Lopez, G. Bissette, H.P. Roffwarg, Rapid eye movement sleep deprivation revives a form of developmentally regulated synaptic plasticity in the visual cortex of post-critical period rats, Neurosci Lett., (2005), in press]. In this study we tested the hypothesis that low-frequency stimulation (LFS) of the fibers of the WM, which usually produces the related form of synaptic plasticity, long-term depression (LTD), will also reflect the reduction in inhibitory tone. We report here that LFS protocols, which in normally sleeping, adolescent rats usually produce either LTD or no change in response magnitude, in REMS-deprived, adolescent rats are more likely to produce LTP.

Age Factors↗
PubMed2002

Roles of inhibitory interneurons in the cerebellar cortex.

The roles of inhibitory interneurons in the cerebellar cortex were investigated. First, Golgi cells were specifically eliminated in transgenic mice in which Golgi cells expressed human interleukin-2 receptor alpha subunit (IL2Ralpha). Injection of exotoxin coupled to anti-IL2Ralpha antibody in the cerebellum of the transgenic mouse eliminated Golgi cells and abolished GABA and synaptic inhibition in the granular layer. After elimination of Golgi cells, acute severe ataxia and subsequent mild motor discoordination were observed. In the latter chronic phase, NMDA receptor-mediated synaptic response was reduced in granule cells. Our findings indicate that elimination of GABAergic inhibition in the granular layer caused overexcitation of granule cells resulting in severe ataxia, and then NMDA receptors in granule cells were downregulated, compensating for the reduction of GABAergic inhibition and improving motor control. In the second part, we report on the regulation mechanism of synaptic plasticity at inhibitory synapses on Purkinje cells (PCs). Inhibitory synaptic transmission on a PC is potentiated after repetitive PC depolarization. This synaptic plasticity (rebound potentiation, RP) was suppressed when a presynaptic neuron was activated during the PC depolarization. This synaptic regulation is unique in the sense that the homosynaptic activity suppresses the induction of synaptic plasticity. The mechanism of how presynaptic activity suppresses RP was examined. GABA released from the presynaptic terminal activated not only GABA(A) receptor but also GABA(B) receptor. The latter was coupled to Gi/o proteins, which downregulated adenylyl cyclase reducing cAMP and inactivated cAMP-dependent protein kinase (PKA). Downregulation of PKA suppressed RP induction.

Animals↗
PubMed2004

Brain plasticity and remodeling of AMPA receptor properties by calcium-dependent enzymes.

Long-term potentiation (LTP) and long-term depression (LTD) are two experimental models of synaptic plasticity that have been studied extensively in the last 25 years, as they may represent basic mechanisms to store certain types of information in neuronal networks. In several brain regions, these two forms of synaptic plasticity require dendritic depolarization, and the amplitude and duration of the depolarization-induced calcium signal are crucial parameters for the generation of either LTP or LTD. The rise in calcium concentration mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to stimulate various calcium-dependent processes that could convert the induction signal into long-lasting changes in synaptic structure and function. According to several lines of experimental evidence, alterations in synaptic function observed with LTP and LTD are thought to be the result of modifications of postsynaptic currents mediated by the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. The question of which type(s) of receptor changes constitutes the basis for the expression of synaptic plasticity is still very much open. Here, we review data relevant to the issue of selective modulation of AMPA receptor properties occurring after learning and memory, environmental enrichment, and synaptic plasticity. We also discuss potential cellular mechanisms whereby calcium-dependent enzymes might regulate AMPA receptor properties during LTP and LTD, focusing on protein kinases, proteases and lipases.

Brain↗
PubMed1998

Neuronal activity induction of the stathmin-like gene RB3 in the rat hippocampus: possible role in neuronal plasticity.

Synaptic activity induces a rapid transcriptional response that is essential for the establishment of long-term neuronal plasticity. Using a differential cloning technique, we have identified a gene induced by seizure activity in the brain as RB3. RB3 is a recently cloned gene belonging to the stathmin family of phosphoproteins. Like SCG10, RB3 is brain-specific, although in situ hybridization results show that the expression of RB3 is more ubiquitous than is that of SCG10. Using genomic DNA sequencing, we show that the 27 amino acid sequence unique to the RB3" transcript is encoded by an alternatively spliced exon, exon 2'. Using a peptide antibody raised against exon 2' to detect RB3" and an anti-Flag antibody to detect an epitope-tagged version of RB3, we show that both proteins are localized to the Golgi apparatus of transfected COS7 cells. Of particular interest, RB3 mRNA, but not SCG10 mRNA, is rapidly induced in the dentate gyrus granule layer of the hippocampus after electrically induced seizure activity as well as stimuli leading to long-term potentiation (LTP). In addition, RB3 mRNA is induced in pheochromocytoma (PC12) cells treated with 250 ng/ml NGF. These results suggest that RB3 may play a role in activity-induced neuronal plasticity and neuronal differentiation.

Alternative Splicing↗
PubMed2006

Fornix lesions decouple the induction of hippocampal arc transcription from behavior but not plasticity.

The immediate-early gene (IEG) Arc is transcribed after behavioral and physiological treatments that induce synaptic plasticity and is implicated in memory consolidation. The relative contributions of neuronal activity and learning-related plasticity to the behavioral induction of Arc remain to be defined. To differentiate the contributions of each, we assessed the induction of Arc transcription in rats with fornix lesions that impair hippocampal learning yet leave cortical connectivity and neuronal firing essentially intact. Arc expression was assessed after exploration of novel environments and performance of a novel water maze task during which normal rats learned the spatial location of an escape platform. During the same task, rats with fornix lesions learned to approach a visible platform but did not learn its spatial location. Rats with fornix lesions had normal baseline levels of hippocampal Arc mRNA, but unlike normal rats, expression was not increased in response to water maze training. The integrity of signaling pathways controlling Arc expression was demonstrated by stimulation of the medial perforant path, which induced normal synaptic potentiation and Arc in rats with fornix lesions. Together, the results demonstrate that Arc induction can be decoupled from behavior and is more likely to indicate the engagement of synaptic plasticity mechanisms than synaptic or neuronal activity per se. The results further imply that fornix lesions may impair memory in part by decoupling neuronal activity from signaling pathways required for long-lasting hippocampal synaptic plasticity.

Animals↗
PubMed2003

Synaptic gain control and homeostasis.

Chronic changes in activity can induce neurons to alter the strength of all their synapses in unison. Although the specific changes that occur appear to vary depending on the experimental preparation, their net effect is to counter the experimentally induced modification of activity. Such adaptive, cell-wide changes in synaptic strength serve to stabilize neuronal activity and are collectively referred to as homeostatic synaptic plasticity. Recent studies have shed light on what triggers homeostatic synaptic plasticity, whether or not it is distinct from other forms of synaptic plasticity and whether or not it occurs in the intact brain.

Action Potentials↗
PubMed2001

[Cellular and molecular mechanisms of memory].

There has been nearly a century of interest in the idea that information is encoded in the brain as specific spatio-temporal patterns of activity in distributed networks and stored as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, the key events in the cellular and molecular mechanisms underlying synaptic plasticity are starting to be identified. They require the activation of specific receptors and of several molecular cascades to convert extracellular signals into persistent functional changes in neuronal connectivity. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. The recent developments in the search for the cellular and molecular mechanisms of memory storage are reviewed.

Gene Expression Regulation↗
PubMed2000

Learning with two sites of synaptic integration.

Since the classical work of D O Hebb 1949 The Organization of Behaviour (New York: Wiley) it is assumed that synaptic plasticity solely depends on the activity of the pre- and the postsynaptic cells. Synapses influence the plasticity of other synapses exclusively via the post-synaptic activity. This confounds effects on synaptic plasticity and neuronal activation and, thus, makes it difficult to implement networks which optimize global measures of performance. Exploring solutions to this problem, inspired by recent research on the properties of apical dendrites, we examine a network of neurons with two sites of synaptic integration. These communicate in such a way that one set of synapses mainly influences the neurons' activity; the other set gates synaptic plasticity. Analysing the system with a constant set of parameters reveals: (1) the afferents that gate plasticity act as supervisors, individual to every cell. (2) While the neurons acquire specific receptive fields the net activity remains constant for different stimuli. This ensures that all stimuli are represented and, thus, contributes to information maximization. (3) Mechanisms for maximization of coherent information can easily be implemented. Neurons with non-overlapping receptive fields learn to fire correlated and preferentially transmit information that is correlated over space. (4) We demonstrate how a new measure of performance can be implemented: cells learn to represent only the part of the input that is relevant to the processing at higher stages. This criterion is termed 'relevant infomax'.

Cell Communication↗
PubMed1999

Preexposure to drug administration context blocks the development of tolerance to sedative effects of diazepam.

The development of tolerance to benzodiazepine (BDZ) and other psychoactive agents such as morphine, alcohol, and barbiturates is thought to be a contingent or learning phenomenon. In a previous report, we demonstrated a positive correlation between the development of tolerance to the sedative effects of diazepam (DZ) and hippocampal synaptic plasticity. The results of the present work show that the development of tolerance to the hypolocomotor action of DZ (5 mg/kg) for 4 days and the associated increase in synaptic plasticity are context specific. Because animal preexposure to the drug administration context blocks both the tolerance sedative effects of DZ and the increased hippocampal synaptic plasticity, observed after 4 days of DZ administration, we propose the increased synaptic plasticity on hippocampal development as one of the biological substrates to the tolerance to DZ. Besides, the continuous administration of DZ did not induce a conditioning opponent response in these animals.

Animals↗
PubMed2005

Ovariectomy-induced disruption of long-term synaptic depression in the hippocampal CA1 region in vivo is attenuated with chronic estrogen replacement.

Endogenous cyclical changes in the levels of estrogen can have marked effects on hippocampal synaptic plasticity. In two experiments, we examined the effect of chronic estrogen loss and replacement following ovariectomy on the induction of bidirectional changes in synaptic plasticity in the CA1 region in vivo. In Experiment 1, ovariectomy carried out either 5 days or 5 weeks before testing impaired the induction of long-term depression (LTD) and but not long-term potentiation (LTP). In Experiment 2, chronic estrogen replacement (0.2 ml of 10 microg injection of 17beta-estradiol every 48 h) over the course of 5 weeks enhanced the magnitude of paired-pulse-induced LTD in the CA1 region but had no effect on the induction of LTP. The results demonstrate that acute and chronic estrogen deprivation disrupted dynamic synaptic plasticity processes in the hippocampal CA1 region and that this disruption was ameliorated by chronic estrogen replacement. The findings are discussed with reference to: (1) the contribution of Ca(2+) regulated synaptic signalling pathways in the CA1 region to estradiol modulation of LTP and LTD and (2) the potential functional significance of ovariectomy-induced changes in synaptic plasticity for learning and memory processes.

Animals↗
PubMed2006

Comparative plasticity of brain synapses in inbred mouse strains.

One niche of experimental biology that has experienced considerable progress is the neurobiology of learning and memory. A key contributor to such progress has been the widespread use of transgenic and 'knockout' mice to elucidate the mechanisms of identifiable phenotypes of learning and memory. Inbred mouse strains are needed to generate genetically modified mice. However, genetic variations between inbred strains can confound the interpretation of cellular neurophysiological phenotypes of mutant mice. It is known that altered physiological strength of synaptic transmission ('synaptic plasticity') can modify and regulate learning and memory. Characterization of the synaptic phenotypes of inbred mouse strains is needed to identify the most appropriate strains to use for generating mutant mouse models of memory function. More importantly, comparative electrophysiological analyses of inbred mice per se can also shed light on which forms of synaptic plasticity underlie particular types of learning and memory. Many such analyses have focused on synaptic plasticity in the hippocampus because of the critical roles of this brain structure in the formation and consolidation of long-term memories. Comparative electrophysiological data obtained from several inbred mouse strains are reviewed here to highlight the following key notions: (1) synaptic plasticity is influenced by the genetic backgrounds of inbred mice; (2) the plasticity of hippocampal synapses in inbred mice is ;tuned' to particular temporal patterns of activity; (3) long-term potentiation, but not long-term depression, is a cellular correlate of behavioural memory performance in some strains; (4) synaptic phenotyping of inbred mouse strains can identify cellular models of memory impairment that can be used to elucidate mechanisms that may cause specific memory deficits.

Animals↗
PubMed2003

Plastic control of striatal glutamatergic transmission by ensemble actions of several neurotransmitters and targets for drugs of abuse.

Long-lasting alterations in the efficacy of glutamatergic synapses, such as long-term potentiation (LTP) and long-term depression (LTD), are prominent models for mechanisms of information storage in the brain. It has been suggested that exposure to drugs of abuse produces synaptic plasticity at glutamatergic synapses that shares many features with LTP and LTD, and that these synaptic changes may play roles in addiction. We have examined the involvement of particular neurotransmitters in synaptic plasticity at glutamatergic synapses within the striatum, a brain region with prominent roles in initiation and sequencing of actions, as well as habit formation. Our studies indicate that multiple neurotransmitters interact to produce striatal synaptic plasticity, and that the relative strength and patterning of the afferent inputs that release the various neurotransmitters determines whether LTP or LTD is activated. Drugs of abuse interact with glutamatergic synaptic plasticity in multiple ways, including alterations in dopamine release and more direct effects on glutamate release and glutamate receptors. We hypothesize that these effects contribute to addiction by facilitating the formation of new, drug-centered habits, and by disruption of more adaptive behaviors.

Animals↗
PubMedDate not supplied

An analysis of contemporary morphological concepts of synaptic remodelling in the CNS: perforated synapses revisited.

Perforated synapses refer to a synaptic type found in the central nervous system. They are characterized by their large size and by a discontinuity of the postsynaptic density when viewed in transverse sections, and by a doughnut or horseshoe shape when viewed in en face views. Of recent morphological studies, one approach has followed their characteristics throughout development and maturity, while others have concentrated on their probable roles in activities including kindling, long-term potentiation, spatial working memory, differential rearing, and the functioning of neuroleptics. An assessment is made of the hypotheses and models that have proved determinative in the emergence of perforated synapses as being significant in synaptic plasticity. Their distribution and frequency are summarized, with emphasis on the importance of unbiased stereological procedures in their analysis. Using three-dimensional approaches various subtypes are recognized. Of these, a complex or fragmented subtype appears of especial significance in synaptic plasticity. Ideas regarding the life-cycle of perforated synapses are examined. The view that they originate from conventional, non-perforated synapses, enlarge, and subsequently split to give rise to a new generation of non-perforated synapses, is critically assessed. According to an alternative model, perforated and non-perforated synapses constitute separate populations from early in their development, each representing complementary forms of synaptic plasticity. An attempt is also made to discover whether synaptic studies on the human brain in normal aging and in Alzheimer's disease throw light on the role of perforated synapses in synaptic plasticity. The loss of synapses in Alzheimer's disease may include a loss of perforated synapses - of particular relevance for an understanding of certain neuropathological conditions.

Aging↗
PubMed1998

Memory suppressor genes: inhibitory constraints on the storage of long-term memory.

Synaptic plasticity, the ability of neurons to alter the strength of their synaptic connections with activity and experience, is thought to play a critical role in memory storage. Molecular studies of gene expression during long-lasting synaptic plasticity related to memory storage initially focused on the identification of positive regulators. More recent work has revealed that the establishment of long-lasting synaptic plasticity and long-term memory also requires the removal of inhibitory constraints. By analogy to tumor suppressor genes, which restrain cell proliferation, we propose that these inhibitory constraints of memory storage, which restrain synapse growth, be termed memory suppressor genes.

Activating Transcription Factor 2↗
PubMed2006

Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase.

Superoxide has been shown to be critically involved in several pathological manifestations of aging animals. In contrast, superoxide also can act as a signaling molecule to modulate signal transduction cascades required for hippocampal synaptic plasticity. Mitochondrial superoxide dismutase (SOD-2 or Mn-SOD) is a key antioxidant enzyme that scavenges superoxide. Thus, SOD-2 may not only prevent aging-related oxidative stress, but may also regulate redox signaling in young animals. We used transgenic mice overexpressing SOD-2 to study the role of mitochondrial superoxide in aging, synaptic plasticity, and memory-associated behavior. We found that overexpression of SOD-2 had no obvious effect on synaptic plasticity and memory formation in young mice, and could not rescue the age-related impairments in either synaptic plasticity or memory in old mice. However, SOD-2 overexpression did decrease mitochondrial superoxide in hippocampal neurons, and extended the lifespan of the mice. These findings increase our knowledge of the role of mitochondrial superoxide in physiological and pathological processes in the brain.

Analysis of Variance↗
PubMed2002

Post-ischaemic long-term synaptic potentiation in the striatum: a putative mechanism for cell type-specific vulnerability.

In the present in vitro study of rat brain, we report that transient oxygen and glucose deprivation (in vitro ischaemia) induced a post-ischaemic long-term synaptic potentiation (i-LTP) at corticostriatal synapses. We compared the physiological and pharmacological characteristics of this pathological form of synaptic plasticity with those of LTP induced by tetanic stimulation of corticostriatal fibres (t-LTP), which is thought to represent a cellular substrate of learning and memory. Activation of N-methyl-D-aspartate (NMDA) receptors was required for the induction of both forms of synaptic plasticity. The intraneuronal injection of the calcium chelator BAPTA [bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate] and inhibitors of the mitogen-activated protein kinase pathway blocked both forms of synaptic plasticity. However, while t-LTP showed input specificity, i-LTP occurred also at synaptic pathways inactive during the ischaemic period. In addition, scopolamine, a muscarinic receptor antagonist, prevented the induction of t-LTP but not of i-LTP, indicating that endogenous acetylcholine is required for physiological but not for pathological synaptic potentiation. Finally, we found that striatal cholinergic interneurones, which are resistant to in vivo ischaemia, do not express i-LTP while they express t-LTP. We suggest that i-LTP represents a pathological form of synaptic plasticity that may account for the cell type-specific vulnerability observed in striatal spiny neurones following ischaemia and energy deprivation.

Acetylcholine↗
PubMed1996

Differential regulation of type I and type VIII Ca2+-stimulated adenylyl cyclases by Gi-coupled receptors in vivo.

Coupling of intracellular Ca2+ to cAMP increases may be important for some forms of synaptic plasticity. The type I adenylyl cyclase (I-AC) is a neural-specific, Ca2+-stimulated enzyme that couples intracellular Ca2+ to cAMP increases. Since optimal cAMP levels may be crucial for some types of synaptic plasticity, mechanisms for inhibition of Ca2+-stimulated adenylyl cyclases may also be important for neuroplasticity. Here we report that Ca2+ stimulation of I-AC is inhibited by activation of Gi-coupled somatostatin and dopamine D2L receptors. This inhibition is due primarily to Gialpha and not betagamma subunits since coexpression of betagamma-binding proteins with I-AC did not affect somatostatin inhibition. However, betagamma released from Gs did inhibit I-AC, indicating that the enzyme can be inhibited by betagamma in vivo. Interestingly, type VIII adenylyl cyclase (VIII-AC), another Ca2+-stimulated adenylyl cyclase, was not inhibited by Gi-coupled receptors. These data indicate that I-AC and VIII-AC are differentially regulated by Gi-coupled receptors and provide distinct mechanisms for interactions between the Ca2+ and cAMP signal transduction systems. We propose that I-AC may be particularly important for synaptic plasticity that depends upon rapid and transient cAMP increases, whereas VIII-AC may contribute to transcriptional-dependent synaptic plasticity that is dependent upon prolonged, Ca2+-stimulated cAMP increases.

Adenylate Cyclase Toxin↗