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PubMed1996

Genetic dissection of structural and functional components of synaptic plasticity. II. Fasciclin II controls presynaptic structural plasticity.

Increased neuronal activity (eag Shaker mutants) and cAMP concentration (dunce mutants) lead to increased synaptic structure and function at the Drosophila neuromuscular junction. Here, we show that the increase in synaptic growth is accompanied by an approximately 50% decrease in synaptic levels of the cell adhesion molecule Fasciclin II (Fas II). This decrease in Fas II is both necessary and sufficient for presynaptic sprouting; FasII mutants that decrease Fas II levels by approximately 50% lead to sprouting similar to eag Shaker and dunce, while transgenes that maintain synaptic Fas II levels suppress sprouting in eag Shaker and dunce. However, FasII mutants that cause a 50% increase in bouton number do not alter synaptic strength; rather, evoked release from single boutons has a reduced quantal content, suggesting that the wild-type amount of release machinery is distributed throughout more boutons.

Animals↗
PubMed1983

Synaptic plasticity within the interpeduncular nucleus after unilateral lesions of the habenula in neonatal rats.

In rats, synaptic terminations of the medial habenular (MH) afferents to the interpeduncular nucleus (IPN) are just beginning to form at the time of birth. The alterations in synaptogenesis resulting from unilateral MH lesions placed in neonatal rats were demonstrated with the autoradiographic and degeneration methods after the operated animals had reached maturity. The distribution of S synapses, en passant MH afferents to the central IPN, is normally 95% ipsilateral to their MH of origin in spite of the fact that their axons cross through the contralateral half of the IPN one or more times. The lesions result in a symmetrical distribution of S synapses from the remaining MH. The density of this projection on each side is equal to the normal ipsilateral density of termination. Crest synapses, present in intermediolateral IPN bilaterally, consist of two endings which contact a narrow dendritic process. Normally, the two endings arise one from each MH at 90% of crest synapses, and two from the same MH at 10%. After unilateral MH lesions in neonates, approximately 96% of crest synapses are formed by two axons from the one remaining MH. At only 4% of crest synapses one or both processes is heterologous, that is, of non-MH origin. These findings demonstrate that synapse formation on IPN neurons preferentially favors MH afferents, both normally and when left-right interaction is precluded by a neonatal unilateral lesion. Left-right interactions normally occur at both the level of the left and right sides of the IPN with regard to S synapses and individual left and right habenular afferents at crest synapses. Plasticity at crest synapses is considerably greater in neonates compared to adult rats. Control of these phenomena can be understood as the interaction of multiple factors. These may include specific determinants localized to the presynaptic axons, particularly prior to synaptogenesis and competition for synaptic space, especially with regard to S synapses and perhaps involving synapse elimination. There is also evidence for postsynaptic determinants both in the separation of synaptic types into separate subnuclei and in the formation of crest synapses in the IPN regardless of the presence of normal or reduced numbers of MH afferents, or their total absence.

Animals↗
PubMed1999

Sending signals from the synapse to the nucleus: possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth.

The ability to learn and form memories depends on specific patterns of synaptic activity and is in part transcription dependent. However, the signal transduction pathways that connect signals generated at synapses with transcriptional responses in the nucleus are not well understood. In the present report, we discuss three signal transduction pathways: the Ca(2+)/calmodulin-dependent kinase (CaMK) pathway, the Ras/ERK pathway, and the SAPK pathways that might function to couple synaptic activity to long-term adaptive responses, in part through the regulation of new gene expression. Evidence suggests that these pathways become activated in response to stimuli that regulate synaptic function such as the influx of extracellular Ca(2+) and certain neurotrophin growth factors such as brain-derived neurotrophic factor. Once activated, the CaMK, Ras/ERK, and SAPK pathways lead to the phosphorylation and activation of transcription factors in the nucleus such as the cyclic AMP response element binding protein (CREB). Genes regulated by CREB or other transcription factor targets of the CaMK, Ras/ERK, and SAPK pathways could mediate important adaptive responses to changes in synaptic activity such as changes in synaptic strength and the regulation of neuronal survival and death.

Animals↗
PubMed2001

Enhancement of short-term synaptic plasticity by prior environmental stress.

All chemical synapses can rapidly up- or downregulate the strength of their connections to reshape the postsynaptic signal, thereby stressing the informational importance of specific neural pathways. It is also true that an organism's environment can exert a powerful influence on all aspects of neural circuitry. We investigated the effect of a prior high-temperature stress on the short-term plasticity of a neuromuscular synapse in the hindleg tibial extensor muscle of Locusta migratoria. We found that the prior stress acted to precondition the synapse by increasing the upper temperature limit for synaptic transmission during a subsequent stressful exposure. As well, preexposure to a stressful high-temperature environment increased short-term facilitation of excitatory junction potentials concurrent with a decrease in excitatory junction potential amplitude and a reduction in its temporal parameters. We conclude that a stressful environment can modify synaptic physiological properties resulting in an enhancement of short-term plasticity of the synapse.

Analysis of Variance↗
PubMed2002

AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila.

Activity-regulated gene expression mediates many aspects of neural plasticity, including long-term memory. In the prevailing view, patterned synaptic activity causes kinase-mediated activation of the transcription factor cyclic AMP response-element-binding protein, CREB. Together with appropriate cofactors, CREB then transcriptionally induces a group of 'immediate early' transcription factors and, eventually, effector proteins that establish or consolidate synaptic change. Here, using a Drosophila model synapse, we analyse cellular functions and regulation of the best known immediate early transcription factor, AP-1; a heterodimer of the basic leucine zipper proteins Fos and Jun. We observe that AP-1 positively regulates both synaptic strength and synapse number, thus showing a greater range of influence than CREB. Observations from genetic epistasis and RNA quantification experiments indicate that AP-1 acts upstream of CREB, regulates levels of CREB messenger RNA, and functions at the top of the hierarchy of transcription factors known to regulate long-term plasticity. A Jun-kinase signalling module provides a CREB-independent route for neuronal AP-1 activation; thus, CREB regulation of AP-1 expression may, in some neurons, constitute a positive feedback loop rather than the primary step in AP-1 activation.

Animals↗
PubMed2005

Plasticity, synaptic strength, and epilepsy: what can we learn from ultrastructural data?

Central nervous system synapses have an intrinsic plastic capacity to adapt to new conditions with rapid changes in their structure. Such activity-dependent refinement occurs during development and learning, and shares features with diseases such as epilepsy. Quantitative ultrastructural studies based on serial sectioning and reconstructions have shown various structural changes associated with synaptic strength involving both dendritic spines and postsynaptic densities (PSDs) during long-term potentiation (LTP). In this review, we focus on experimental studies that have analyzed at the ultrastructural level the consequences of LTP in rodents, and plastic changes in the hippocampus of experimental models of epilepsy and human tissue obtained during surgeries for intractable temporal lobe epilepsy (TLE). Modifications in spine morphology, increases in the proportion of synapses with perforated PSDs, and formation of multiple spine boutons arising from the same dendrite are the possible sequence of events that accompany hippocampal LTP. Structural remodeling of mossy fiber synapses and formation of aberrant synaptic contacts in the dentate gyrus are common features in experimental models of epilepsy and in human TLE. Combined electrophysiological and ultrastructural studies in kindled rats and chronic epileptic animals have indicated the occurrence of seizure- and neuron loss-induced changes in the hippocampal network. In these experiments, the synaptic contacts on granule cells are similar to those described for LTP. Such changes could be associated with enhancement of synaptic efficiency and may be important in epileptogenesis.

Animals↗
PubMed2006

Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function.

The ability of exercise to benefit neuronal and cognitive plasticity is well recognized. This study reveals that the effects of exercise on brain neuronal and cognitive plasticity are in part modulated by a central source of insulin-like growth factor-I. Exercise selectively increased insulin-like growth factor-I expression without affecting insulin-like growth factor-II expression in the rat hippocampus. To determine the role that insulin-like growth factor-I holds in mediating exercise-induced neuronal and cognitive enhancement, a specific antibody against the insulin-like growth factor-I receptor was used to block the action of insulin-like growth factor-I in the hippocampus during a 5-day voluntary exercise period. A two-trial-per-day Morris water maze was performed for five consecutive days, succeeded by a probe trial 2 days later. Blocking hippocampal insulin-like growth factor-I receptors did not significantly attenuate the ability of exercise to enhance learning acquisition, but abolished the effect of exercise on augmenting recall. Blocking the insulin-like growth factor-I receptor significantly reversed the exercise-induced increase in the levels of brain-derived neurotrophic factor mRNA and protein and pro-brain-derived neurotrophic factor protein, suggesting that the effects of insulin-like growth factor-I may be partially accomplished by modulating the precursor to the mature brain-derived neurotrophic factor. A molecular analysis revealed that exercise significantly elevated proteins downstream to brain-derived neurotrophic factor activation important for synaptic function, i.e. synapsin I, and signal transduction cascades associated with memory processes, i.e. phosphorylated calcium/calmodulin protein kinase II and phosphorylated mitogen-activated protein kinase II. Blocking the insulin-like growth factor-I receptor abolished these exercise-induced increases. Our results illustrate a possible mechanism by which insulin-like growth factor-I interfaces with the brain-derived neurotrophic factor system to mediate exercise-induced synaptic and cognitive plasticity.

Animals↗
PubMed1990

Robust synaptic plasticity of striatal cells following partial deafferentation.

Partial ablation of the cerebral cortical input to the neostriatum generates a rapid lasting effect on the size of remaining synaptic sites. The neocortex was lesioned in adult rats and the neostriatum was analyzed for effects on remaining spines of principal cells during the period from 2 to 40 days. There was an increase in the size of spine heads, boutons and synaptic contact sites. The spine heads became very complex and a corresponding bouton enlargement was accompanied by an increase in the number of synaptic vesicles. By two days, the average profile length of postsynaptic membrane densities (PSDs) had increased by 25% representing an equivalent 50% increase in synaptic contact area. The number of synaptic sites was reduced on each principal neuron of the lesioned group. Comparison of the number of sites per unit volume to their average contact area revealed a reciprocal relationship indicating a conservation in the total synaptic contact area on each neuron. This effect was consistent for all postsurgical days. The lack of a significant return of synaptic number by 40 days indicates that axonal sprouting is not a major factor in neuronal plasticity in the adult striatum. The rapid increase in the size of spines, boutons and synaptic sites at remaining connections suggests that dendrites are the first to initiate the plasticity response in adult neurons through postsynaptic attachments and their corresponding receptor structure. The underlying mechanism of this plasticity may be through a conservation of macromolecules forming postsynaptic membrane specializations on target neurons. Remaining axons appear to follow the dendritic response with a plasticity generating presynaptic appositional specializations to match the contact area of the postsynaptic site.

Animals↗
PubMed2005

Short-term synaptic plasticity during development of rat mossy fibre to granule cell synapses.

Changes occur during the postnatal development of the rat glutamatergic mossy fibre to granule cell synapse: to the morphology of synapses, glutamate transporter expression, AMPA receptor expression and the kinetics of AMPA receptor-mediated synaptic transmission. For example, both the rise and decay times of AMPA receptor-mediated excitatory postsynaptic currents significantly shorten. To further define the development of mossy fibre to granule cell synaptic transmission, the properties and mechanisms of short-term plasticity have been described. The characterization of short-term plasticity will aid our understanding of the mechanisms that define the parameters of synaptic transmission during development and furthermore short-term plasticity may play an important role in determining information transfer between mossy fibres and granule cells. In response to pairs of stimuli (2-100-ms interval), depression (second excitatory postsynaptic current amplitude smaller than the first) was observed at both mature (older than 40 postnatal days) and immature (between 8 and 12 postnatal days) synapses. The degree of depression was similar at both stages of development, although recovery from depression was slower at mature synapses (tau 22 vs 12.5 ms). Several experimental approaches (coefficient of variation, low-affinity antagonists and cyclothiazide) suggest that depression at immature synapses results from multiple mechanisms. At mature synapses, postsynaptic receptor desensitization appears to be the major cause of depression.

Animals↗
PubMed1995

Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis.

Structural change in the hippocampal formation has become popular as a proposed neurobiological substrate for schizophrenic disorders. It is postulated that behavioral plasticity in the form of long-term potentiation of hippocampal synaptic transmission is an attractive putative mechanism for the mediation of transient psychosis. Moreover, the disturbed hippocampal neuroarchitecture found in schizophrenic brain may be susceptible to potentiation and dysfunctional to the degree that delusions and hallucinations develop. Partial and selective blockade of the receptors mediating potentiation may prove to be an efficient means of preventing psychotic episodes and avoiding further damage to the involved network. Basic research, utilizing experimental models such as intraventricular kainic acid injection, may help to clarify the anatomical and physiological substrate of psychosis.

Arousal↗
PubMed1979

Biochemical and physiological studies of long-term synaptic plasticity.

High frequency stimulation of fiber systems in the mammalian hippocampus produces a semipermanent increase in synaptic efficacy. This effect, long-term potentiation (LTP), has been of considerable interest as a potential substrate of memory due to its rapid onset and extreme persistence. Experiments are described that indicate that the locus of LTP is confined to the synaptic complex of the fibers stimulated; further, Ca2+ is shown to be essential for the initiation of LTP and may play a role in triggering this increase in synaptic efficiency. Data from biochemical analyses of LTP indicate that a 40,000 dalton synaptic membrane protein shows a highly reliable change in its endogenous phosphorylation following high frequency hippocampal stimulation. Phosphorylase kinase, a Ca2+ sensitive enzyme, is shown to specifically catalyse the phosphorylation of this 40,000 dalton protein. The data are discussed in terms of a working model in which the Ca2+ dependent phosphorylation of the 40,000 dalton protein produced by high frequency stimulation is a biochemical intermediate in the production of LTP.

Animals↗
PubMed1999

The role of cell adhesion molecules in synaptic plasticity and memory.

Studies in the past few years suggest that cell adhesion molecules may play signaling as well as structural roles at adult synapses during plasticity. The observation that many adhesion molecules are expressed both pre-synaptically and post-synaptically raises the possibility that information about synaptic activity might simultaneously be communicated to both sides of the synapse, circumventing the need for distinct anterograde and retrograde messengers.

Animals↗
PubMed2005

Inactivation of C/EBP transcription factors specifically affects the synaptic plasticity of a common snail neuron.

Our previous studies showed that the acquisition of nociceptive sensitization in common snails is accompanied by long-term facilitation of synaptic transmission in defensive behavior command neuron LP11, this being dependent on translation and transcription processes. The characteristics of the neurochemical mechanisms of plasticity in the different sensory inputs of this nerve cell were identified. The mechanisms of induction of synaptic facilitation of the responses of neuron LP11 to chemical sensory stimulation of the snail's head involved NMDA glutamate receptors, serotonin receptors, cAMP, and serotonin-modulated transcription-regulating protein SMP-69. The mechanisms of induction of synaptic facilitation of another sensory input of the neuron--from tactile receptors on the head - involved protein kinase C. The present study addresses the involvement of C/EBP transcription factors (CCAAT-enhancer-binding protein) in the processes of synapse-specific plasticity of neuron LP11 during the acquisition of sensitization in snails. C/EBP was inactivated using oligonucleotides specifically binding to these proteins. The results showed that acquisition of sensitization during intracellular administration of oligonucleotides led to the selective suppression of synaptic facilitation in the responses of neuron LP11 to chemical sensory stimulation of the snail's head. Synaptic facilitation in the responses to tactile stimulation of the head or foot developed as in neurons in control sensitized snails. It is suggested that C/EBP transcription factor is selectively involved in the mechanisms of synapse-specific plasticity of the sensory input of neuron LP11 from chemoreceptors on the head during the acquisition of sensitization in snails.

Action Potentials↗
PubMed2004

[Transcription factors C/EBP inhibition specifically affects synaptic plasticity in the snail's neuron].

In our previous investigations it was found that nociceptive sensitization is followed by a long-term facilitation of synaptic transmission in command neuron of defence behavior. The facilitation is translation- and transcription-dependent. Features of plasticity neurochemical mechanisms of different sensory inputs in the neural cells were determined. NMDA glutamate receptors, serotonin receptors, cAMP as well as serotonin-modulated protein SMP-69 are involved in mechanisms of induction of neural response facilitation in LPl 1 neuron evoked by chemical sensory stimulation of snail head. Protein kinase C is involved in synaptic facilitation-induction mechanisms from other sensory neural input--tactile receptors of snail "head". In this work, participation of C/EBP (CCAAT-enhancing-binding protein) immediate early gene transcription factor was established in mechanisms of synapse-specific plasticity during sensitization in LPl 1 neuron in snail Helix lucorum. Specific binding with C/EBP oligonucleotides were used as C/EBP inhibitors. It was found that sensitization during intracellular oligonucleotide injection selectively suppressed synaptic facilitation in LPl 1 neuron responses evoked by chemical sensory stimulation of snail "head". At the same time, development of synaptic facilitation of the neuron responses evoked by tactile stimulation of snail head or foot was the same as in control sensitized snails. It seems that C/EBP transcription factor is selectively involved in mechanisms of synapse-specific plasticity of sensory input in LPl 1 neuron from snail head chemoreceptors.

Animals↗
PubMed1998

Selective synaptic plasticity within the cerebellar cortex following complex motor skill learning.

Complex motor skill learning, but not mere motor activity, leads to an increase in synapse number within the cerebellar cortex. The present experiment used quantitative electron microscopy to determine which synapse types were altered in number. Adult female rats were allocated to either an acrobatic condition (AC), a voluntary exercise condition (VX), or an inactive condition (IC). AC animals were trained to traverse an elevated obstacle course requiring substantial motor coordination to complete. VX animals were housed with unlimited access to running wheels and IC animals received no motor training but were handled briefly each day. Results showed the AC animals to have significantly more parallel fiber to Purkinje cell synapses than both the VX and IC animals. No other synapse type was significantly altered. Thus, the learning-dependent increase in synapse number observed within the cerebellar cortex is accomplished primarily through the addition of parallel fiber synapses.

Analysis of Variance↗
PubMed2003

Alpha1E-containing Ca2+ channels are involved in synaptic plasticity.

Long-term potentiation (LTP) is the most prominent model for the molecular and cellular mechanisms of learning and memory. Two main forms of LTP have been distinguished. The N-methyl-D-aspartate-receptor-dependent forms of LTP have been studied most extensively, whereas much less is known about N-methyl-D-aspartate-receptor-independent forms of LTP. This latter type of LTP was first described at the mossy fiber synapses in the hippocampus and subsequently at parallel fiber synapses in the cerebellum as well as at corticothalamic synapses. These presynaptic forms of LTP require a rise in the intraterminal calcium concentration, but the channel through which calcium passes has not been identified. By using pharmacological tools as well as genetic deletion, we demonstrate here that alpha1E-containing voltage-dependent calcium channels (VDCCs) shift the threshold for mossy fiber LTP. The channel is not involved in the expression mechanism, but it contributes to the calcium influx during the induction phase. Indeed, optical recordings directly show the presence and the function of alpha1E-containing VDCCs at mossy fiber terminals. Hence, a previously undescribed role for alpha1E-containing VDCCs is suggested by these results.

Animals↗
PubMed2005

Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala.

In experiments designed to investigate the relationship between stress and the acquisition of new fear memories, it was found that previous exposure to a restraint session increased fear conditioning in a contextual fear paradigm. Moreover, the infusion of bicuculline, a competitive antagonist of GABAA receptors, into the basolateral amygdala complex (BLA), but not into the central amygdaloid nucleus, induced the same behavioral effect. Pretreatment with midazolam (MDZ), a positive modulator of GABAA sites, prevented the facilitating influence on fear memory of both stress and GABAA receptor blockade in the BLA. These data suggest that facilitation of fear conditioning could be causally related to increased neuronal excitability attributable to depressed GABAergic inhibition in the BLA. To test this hypothesis, evoked potentials were studied in brain slices from stressed animals. Potentials evoked in the BLA by single stimuli applied to the external capsule showed multispike responses, suggestive of GABAergic disinhibition. These multiple responses were no longer evident after the slices were perfused with diazepam or if the stressed animals were pretreated with MDZ. In slices from stressed rats, paired-pulse inhibition (GABA dependent) was suppressed. Also, in stressed animals, long-term potentiation (LTP) was induced with a single train of high-frequency stimulation, which did not induce LTP in control rats. Moreover, MDZ pretreatment prevented the facilitating influence of stress on LTP induction. All of these findings support the hypothesis that previous stress attenuates inhibitory GABAergic control in the BLA, leading to neuronal hyperexcitability and increased plasticity that facilitates fear learning.

Amygdala↗