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PubMed2003

Equalization of synaptic efficacy by activity- and timing-dependent synaptic plasticity.

In many neurons, synapses increase in strength as a function of distance from the soma in a manner that appears to compensate for dendritic attenuation. This phenomenon requires a cooperative interaction between local factors that control synaptic strength, such as receptor density and vesicle release probability, and global factors that affect synaptic efficacy, such as attenuation and boosting by active membrane conductances. Anti-spike-timing-dependent plasticity, in combination with nonassociative synaptic potentiation, can accomplish this feat even though it acts locally and independently at individual synapses. Analytic computations and computer simulations show that this combination of synaptic plasticity mechanisms equalizes the efficacy of synapses over an extended dendritic cable by adjusting local synaptic strengths to compensate for global attenuation.

Action Potentials↗

PubMed2000

The neurotrophin hypothesis for synaptic plasticity.

The neurotrophin hypothesis proposes that neurotrophins participate in activity-induced modification of synaptic transmission. Increasingly, evidence indicates that the synthesis, secretion and actions of neurotrophins on synaptic transmission are regulated by electrical activity and that neurotrophins themselves can acutely modify synaptic efficacy. Neurotrophins appear to exert either a permissive or instructive role on activity-dependent synaptic potentiation and depression, which depends on the particular synaptic connections and developmental stages. The characteristics of synaptic changes that are induced by neurotrophins suggest that this family of proteins is crucial for providing a molecular background in which activity-dependent plasticity can occur at selective synaptic sites within the neural network.

Animals↗

PubMed2005

Effect of myristoylated alanine-rich C kinase substrate (MARCKS) overexpression on hippocampus-dependent learning and hippocampal synaptic plasticity in MARCKS transgenic mice.

The myristoylated alanine-rich C kinase substrate (MARCKS) is a primary substrate of protein kinase C (PKC) thought to regulate membrane-filamentous actin cytoskeletal plasticity in response to PKC activity in the regulation of synaptic efficacy. We have recently reported that MARCKS expression is significantly elevated (45%) in the hippocampus of DBA/2J mice, which exhibit impaired hippocampus-dependent learning and hippocampal long-term potentiation (LTP), compared with C57BL/6J mice. The latter finding led us to hypothesize that elevations in MARCKS expression are detrimental to hippocampal plasticity and function. To assess this more directly, we examined hippocampal (CA1) paired-pulse facilitation and LTP, and hippocampus-dependent learning in mice overexpressing MARCKS through the expression of a human MARCKS transgene (Tg+). The human MARCKS protein was confirmed to be expressed in the hippocampus of Tg+ mice but not in Tg- mice. Schaffer collateral paired-pulse facilitation, input-output responses, and LTP did not differ between Tg+ and Tg- mice, indicating that neurotransmitter release, short-term, and long-term synaptic plasticity are not impaired by MARCKS overexpression. In the Morris water maze, Tg+ mice exhibited a mild but significant spatial learning impairment during initial acquisition, and a more severe impairment during reversal training. Tg+ did not exhibit impaired swim speed or visible platform performance relative to Tg- mice, indicating the absence of gross sensorimotor deficits. Fear conditioning to either context or cue was not impaired in Tg+ mice. Behavioral deficits could not be attributed to differences in hippocampal PKC isozyme (alpha beta(II), gamma, epsilon, zeta) or calmodulin expression, or alterations in hippocampal cytoarchitecture or infrapyramidal mossy fiber limb length. Collectively, these results indicate that elevations in MARCKS expression are detrimental to specific aspects of hippocampal function.

Animals↗

PubMed2002

Activity-dependent synaptic plasticity: insights from neuromuscular junctions.

Experience-dependent editing shapes synaptic connections throughout the developing nervous system, but the underlying cellular mechanisms remain poorly understood. A useful model synapse for addressing these mechanisms is the neuromuscular junction, the connection between spinal motor neurons and skeletal muscle fibers. Here the authors review current ideas about the role of activity in editing neuromuscular synaptic connections. A variety of new tools are being used to address some unanswered questions in vivo and in vitro. Understanding activity-dependent plasticity at developing neuromuscular synapses may reveal how neural circuits in the central nervous system are altered by experience throughout life.

Animals↗

PubMed1996

Ionotropic glutamate receptors. Their possible role in the expression of hippocampal synaptic plasticity.

In the brain, most fast excitatory synaptic transmission is mediated through L-glutamate acting on postsynaptic ionotropic glutamate receptors. These receptors are of two kinds--the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate (non-NMDA) and the N-methyl-D-aspartate (NMDA) receptors, which are thought to be colocalized onto the same postsynaptic elements. This excitatory transmission can be modulated both upward and downward, long-term potentiation (LTP) and long-term depression (LTD), respectively. Whether the expression of LTP/LTD is pre-or postsynaptically located (or both) remains an enigma. This article will focus on what postsynaptic modifications of the ionotropic glutamate receptors may possibly underly long-term potentiation/depression. It will discuss the character of LTP/ LTD with respect to the temporal characteristics and to the type of changes that appears in the non-NMDA and NMDA receptor-mediated synaptic currents, and what constraints these findings put on the possible expression mechanism(s) for LTP/LTD. It will be submitted that if a modification of the glutamate receptors does underly LTP/LTD, an increase/ decrease in the number of functional receptors is the most plausible alternative. This change in receptor number will have to include a coordinated change of both the non-NMDA and the NMDA receptors.

Animals↗

PubMed2006

Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala.

Learning and memory depend on signaling molecules that affect synaptic efficacy. The cytoskeleton has been implicated in regulating synaptic transmission but its role in learning and memory is poorly understood. Fear learning depends on plasticity in the lateral nucleus of the amygdala. We therefore examined whether the cytoskeletal-regulatory protein, myosin light chain kinase, might contribute to fear learning in the rat lateral amygdala. Microinjection of ML-7, a specific inhibitor of myosin light chain kinase, into the lateral nucleus of the amygdala before fear conditioning, but not immediately afterward, enhanced both short-term memory and long-term memory, suggesting that myosin light chain kinase is involved specifically in memory acquisition rather than in posttraining consolidation of memory. Myosin light chain kinase inhibitor had no effect on memory retrieval. Furthermore, ML-7 had no effect on behavior when the training stimuli were presented in a non-associative manner. Anatomical studies showed that myosin light chain kinase is present in cells throughout lateral nucleus of the amygdala and is localized to dendritic shafts and spines that are postsynaptic to the projections from the auditory thalamus to lateral nucleus of the amygdala, a pathway specifically implicated in fear learning. Inhibition of myosin light chain kinase enhanced long-term potentiation, a physiological model of learning, in the auditory thalamic pathway to the lateral nucleus of the amygdala. When ML-7 was applied without associative tetanic stimulation it had no effect on synaptic responses in lateral nucleus of the amygdala. Thus, myosin light chain kinase activity in lateral nucleus of the amygdala appears to normally suppress synaptic plasticity in the circuits underlying fear learning, suggesting that myosin light chain kinase may help prevent the acquisition of irrelevant fears. Impairment of this mechanism could contribute to pathological fear learning.

Amygdala↗

PubMed2000

Modeling synaptic plasticity in conjuction with the timing of pre- and postsynaptic action potentials.

We present a spiking neuron model that allows for an analytic calculation of the correlations between pre- and postsynaptic spikes. The neuron model is a generalization of the integrate-and-fire model and equipped with a probabilistic spike-triggering mechanism. We show that under certain biologically plausible conditions, pre- and postsynaptic spike trains can be described simultaneously as an inhomogeneous Poisson process. Inspired by experimental findings, we develop a model for synaptic long-term plasticity that relies on the relative timing of pre- and post-synaptic action potentials. Being given an input statistics, we compute the stationary synaptic weights that result from the temporal correlations between the pre- and postsynaptic spikes. By means of both analytic calculations and computer simulations, we show that such a mechanism of synaptic plasticity is able to strengthen those input synapses that convey precisely timed spikes at the expense of synapses that deliver spikes with a broad temporal distribution. This may be of vital importance for any kind of information processing based on spiking neurons and temporal coding.

Action Potentials↗

PubMed1999

Input-and layer-dependent synaptic plasticity in the rat perirhinal cortex in vitro.

The perirhinal cortex is crucially important in several forms of memory. Whilst it is important to understand the underlying mechanisms of this role in memory, little is known about the synaptic physiology or plasticity of this region of transitional cortex. In this study, we recorded evoked field potentials in superficial layers (approximately layer I) of the perirhinal cortex in vitro. One stimulating electrode was placed on the temporal side and the other on the entorhinal side of the rhinal sulcus in either the superficial or intermediate layers (approximately layers II/III). Paired stimuli resulted in depression of the second response. Paired-pulse depression was maximal at a 200-ms interpulse interval. Low-frequency stimulation resulted in synaptic depression, which returned to baseline within 60 min. The magnitude of both paired-pulse depression and low-frequency stimulation-induced depression was significantly greater at synapses activated from the temporal intermediate pathway than the other three pathways. Long-term potentiation, stable for at least 60 min, was induced by high-frequency stimulation of intermediate but not superficial pathways. Long-lasting depression (depotentiation) was induced by low-frequency stimulation following the induction of long-term potentiation. The induction of both long-term potentiation and depotentiation was N-methyl-D-aspartate receptor dependent. The group I/II metabotropic glutamate receptor antagonist (S)-alpha-methyl-4-carboxyphenylglycine was without effect on either of these forms of plasticity. Thus, both long- and short-lasting forms of synaptic plasticity exist at synapses in the perirhinal cortex, and these may mediate the changes in neuronal responses associated with visual recognition memory.

2-Amino-5-phosphonovalerate↗

PubMed2001

Visualization of changes in presynaptic function during long-term synaptic plasticity.

Controversy exists regarding the site of modification of synaptic transmission during long-term plasticity in the mammalian hippocampus. Here we used a fluorescent marker of presynaptic activity, FM 1-43, to directly image changes in presynaptic function during both short-term and long-term forms of plasticity at presynaptic boutons of CA3-CA1 excitatory synapses in acute hippocampal slices. We demonstrated enhanced presynaptic function during long-term potentiation (LTP) induced either chemically (with tetraethylammonium), or by high-frequency (200-Hz) electrical stimulation. Both of these forms of LTP required activation of L-type voltage-gated calcium channels and NMDA receptors in the postsynaptic CA1 neuron. These results thus implied that a long-lasting increase in the efficacy of synaptic transmission is likely to depend, at least in part, on enhanced transmitter release from the presynaptic neuron.

Animals↗

PubMed2002

A fresh look at the role of CaMKII in hippocampal synaptic plasticity and memory.

Advances in molecular, genetic, and cell biological techniques have allowed neuroscientists to delve into the cellular machinery of learning and memory. The calcium and calmodulin-dependent kinase type II (CaMKII) is one of the best candidates for being a molecular component of the learning and memory machinery in the mammalian brain. It is present in abundance at synapses and its enzymatic properties and responsiveness to intracellular Ca(2+) fit a model whereby Ca(2+) currents activate the kinase and lead to changes in synaptic efficacy. Indeed, such plastic properties of synapses are thought to be important for memory formation. Genetic analysis of the alpha isoform of CaMKII in mice support the hypothesis that CaMKII signaling is required to initiate the formation of new spatial memories in the hippocampus. CaMKII is also required for the correct induction of long-term potentiation (LTP) in the hippocampus, consistent with the widely held belief that LTP is a mechanism for learning and memory. Recent cell biological, genetic, and physiological analyses suggest that one of the cellular explanations for LTP and CaMKII function might be the trafficking of AMPA-type receptors to synapses in response to neural activity.

Animals↗

PubMed2003

A model synapse that incorporates the properties of short- and long-term synaptic plasticity.

We propose a general computer model of a synapse, which incorporates mechanisms responsible for the realization of both short- and long-term synaptic plasticity-the two forms of experimentally observed plasticity that seem to be very significant for the performance of neuronal networks. The model consists of a presynaptic part based on the earlier 'double barrier synapse' model, and a postsynaptic compartment which is connected to the presynaptic terminal via a feedback, the sign and magnitude of which depend on postsynaptic Ca(2+) concentration. The feedback increases or decreases the amount of neurotransmitter which is in a ready for release state. The model adequately reproduced the phenomena of short- and long-term plasticity observed experimentally in hippocampal slices for CA3-CA1 synapses. The proposed model may be used in the investigation of certain real synapses to estimate their physiological parameters, and in the construction of realistic neuronal networks.

Animals↗

PubMed2005

Selective cholinergic immunolesioning affects synaptic plasticity in developing visual cortex.

Cholinergic neurotransmission is known to affect activity-dependent plasticity in various areas, including the visual cortex. However, relatively little is known about the exact role of subcortical cholinergic inputs in the regulation of plastic events in this region during early postnatal development. In the present study, synaptic transmission and plasticity in the developing visual cortex were studied following selective immunotoxic removal of the basal forebrain cholinergic afferents in 4-day-old rat pups. The lesion produced dramatic cholinergic neuronal and terminal fibre loss associated with decreased mRNA levels for the M1 and M2 muscarinic receptors, as well as clear-cut impairments of long-term potentiation (LTP) in visual cortex slices. Indeed, after theta burst stimulation of layer IV a long-term depression (LTD) instead of an LTP was induced in immunolesioned slices. This functional change appears to be due to the lack of cholinergic input as exogenous application of acetylcholine prevented the shift from LTP to LTD. In addition, lesioned rats showed an increased sensitivity to acetylcholine (ACh). While application of 20 microm ACh produced a depression of the field potential in immunolesioned rat slices, in order to observe the same effect in control slices we had to increase ACh concentration to up to 200 microm. Taken together, our results indicate that deprivation of cholinergic input affects synaptic transmission and plasticity in developing visual cortex, suggesting that the cholinergic system could play an active role in the refinement of the cortical circuitry during maturation.

Acetylcholine↗

PubMed1999

A shift in protein S-palmitoylation, with persistence of growth-associated substrates, marks a critical period for synaptic plasticity in developing brain.

In the mammalian cortex, the initial formation of synaptic connections is followed by a prolonged period during which synaptic circuits are functional, but retain an elevated capacity for activity-dependent remodeling and functional plasticity. During this period, synaptic terminals appear fully mature, morphologically and physiologically. We show here, however, that synaptic terminals during this period are distinguished by their simultaneous accumulation of multiple growth-associated proteins at levels characteristic of axonal growth cones, and proteins involved in synaptic transmitter release at levels characteristic of adult synapses. We show further that newly formed synapses undergo a switch in the dynamic S-palmitoylation of proteins early in the critical period, which includes a large and specific decrease in the palmitoylation of GAP-43 and other major substrates characteristic of growth cones. Previous studies have shown that a similar reduction in ongoing palmitoylation of growth cone proteins is sufficient to stop advancing axons in vitro, suggesting that a developmental switch in protein S-palmitoylation serves to disengage the molecular machinery for axon extension in the absence of local triggers for remodeling during the critical period. Only much later does a decline in the availability of major growth cone components mark the molecular maturation of cortical synapses at the close of the critical period.

Aging↗

PubMed1992

Anatomical evidence of synaptic plasticity in the cochlear nuclei of white-deaf cats.

Synapses are dynamic structures reflecting environmental events. It was observed that densities associated with apposing synaptic membranes were altered in response to changing conditions of auditory stimulation (Gulley et al. 1978. J. Comp. Neurol. 180: 707-742). Synapses also exhibit plasticity during early development of the auditory system (Larsen and Pappas, 1985. Proceedings: 43rd Annual Meeting of the Electron Microscopy Society of America, pp. 493-494). Larsen and Pappas reported that, in young kittens, the end bulb of Held (EBH) terminal was distinguished by excessive density at apposing synaptic membranes which assume gradually the pattern observed in adult cats. The maturation of synapses parallels emerging function and may depend upon auditory stimulation (Larsen and Kirchhoff, 1987. Neurosci. Abstr. 13: 1260). Larsen and Kirchhoff found that EBH synapses on large spherical cells of white-deaf cats resembled the immature synapses found in young kittens (Fig. 1). They also found terminals that had an increased number and length of the membrane densities associated with synapses. Because the number of synaptic vesicles in these presynaptic terminals was equivalent to the number of vesicles found in normal-hearing cats, Larsen and Kirchhoff (1987) suggest that this is evidence of synaptic plasticity. We have completed a quantitative study of the synapses of EBH terminals found in adult cats that had been deaf for at least 3 years.

Albinism↗

PubMed1997

Metaplasticity: a new vista across the field of synaptic plasticity.

Over the past 20 years there has been an increasing understanding of the properties and mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic efficacy, putative learning and memory mechanisms in the mammalian brain. More recently, however, it has become apparent that synaptic activity can also elicit persistent neuronal responses not manifest as changes in synaptic strength. Some of these changes may nonetheless modify the ability of synapses to undergo strength changes in response to subsequent episodes of synaptic activity. This kind of activity-dependent modulatory plasticity we have termed "metaplasticity". Metaplasticity has been observed physiologically as an inhibition of LTP and concomitant facilitation of LTD by prior N-methyl-D-aspartate receptor activation or, conversely, a facilitation of LTP induction by prior metabotropic glutamate receptor activation. The examples of metaplasticity described to date are input specific, and last as long as several hours. The mechanisms underlying such phenomena remain to be fully characterized, although some likely possibilities are an altered N-methyl-D-aspartate receptor function, altered calcium buffering, altered states of kinases or phosphatases, and a priming of protein synthesis machinery. While some details vary, experimentally observed metaplasticity bears some similarity to the "sliding threshold" feature of the Bienenstock, Cooper and Munro model of experience-dependent synaptic plasticity. Metaplasticity may serve several functions including (1) providing a way for synapses to integrate a response across temporally spaced episodes of synaptic activity and (2) keeping synapses within a dynamic functional range, and thus preventing them from entering states of saturated LTP or LTD.

Animals↗

PubMed1995

Temporal constraints in associative synaptic plasticity in hippocampus and neocortex.

We present comparative experimental evidence for the induction of synaptic potentiation and depression in organotypic cultures of hippocampus and in visual cortex in vitro and in vivo. The effects of associative pairings on the efficacy of synaptic transmission are analyzed as a function of the temporal delay between presynaptic activity and post-synaptic changes imposed in membrane potential. Synchronous association at a low temporal frequency (< 0.5 Hz) between presynaptic input and postsynaptic depolarization resulted in homosynaptic potentiation of functionally identified postsynaptic potentials in the three types of preparation. Synchronous pairing of afferent activity with hyperpolarization of the postsynaptic cell resulted in homosynaptic depression in visual cortex in vivo and in vitro. An associative form of depression was induced in hippocampus when the test input was followed repeatedly with a fixed-delay postsynaptic depolarization imposed either by intracellular current injection or synaptically. The latter process might play a significant role in heterosynaptic plasticity in visual cortex in vivo and in vitro, if it is assumed that associative depression still operates in visual cortex a few seconds after the initial surge of calcium in the postsynaptic cell. We conclude that the precise timing between presynaptic activity and polarization changes in postsynaptic membrane potential up- and down-regulates the efficacy of active pathways.

Adult↗

PubMed2004

Synaptic plasticity of local connections in rat motor cortex.

This paper reviews studies that investigated mechanisms of the induction of long-term synaptic efficacy increase in local horizontal connections in slices of adult rat motor cortex. Long-term potentiation (LTP) could be induced by electrical stimulation of afferents using theta burst stimulation (TBS) conditionally, when synaptic inhibition was transiently blocked by focal application of GABA(A) receptor antagonist. Robust, long-lasting enhancement of synaptic transmission in horizontal connections was induced by brief application of the potassium channel blocker, tetraethylammonium (TEA, 25 mM), to the incubation medium. This TEA-LTP could be blocked by nifedipine, a voltage-dependent calcium channel blocker. A transient exposure of slices to elevated extracellular calcium (5 mM) resulted in a long-lasting enhancement of responses, termed Ca-LTP, which could be blocked by the antagonist of NMDA receptors, APV. The induction of both TEA-LTP and Ca-LTP, could be prevented by inhibitors of the extracellular signal regulated kinase (ERK) cascade U0126 and PD98059. A transient activation of the ERK, 15 min after application of TEA or elevated [Ca2+], was demonstrated using immunofluorescence. Both forms of plasticity could also be prevented by the inhibitor of cAMP-dependent protein kinases (PKA), Rp-cAMPS. These studies indicate the involvement of the ERK and PKA signaling mechanisms in synaptic plasticity of the motor cortex in vitro. Since LTP in horizontal connections of the motor cortex has previously been shown to be related to the acquisition of a motor skill, it is suggested that the ERK and PKA signaling pathways may be involved in motor learning.

Animals↗

PubMed1999

Synaptic plasticity at thalamocortical synapses in developing rat somatosensory cortex: LTP, LTD, and silent synapses.

Thalamocortical synaptic transmission in the rat's primary somatosensory (S1) cortex is modified by sensory experience during a critical period early in life. Despite the importance of such plasticity for the maturation of thalamocortical circuits, the synaptic basis of this plasticity is unknown. Here, we review evidence suggesting that long-term potentiation and depression (LTP and LTD) of thalamocortical synaptic transmission may be involved in this plasticity. In an in vitro slice preparation, thalamocortical synaptic responses exhibit N-methyl-D-aspartate (NMDA) receptor-dependent LTP and LTD during a developmental period similar to the critical period in vivo. The inability to induce LTP and LTD after the critical period may result in part from a developmental reduction in the duration of NMDA receptor currents. In addition, during the critical period many thalamocortical synapses exhibit NMDA receptor currents but no detectable AMPA receptor currents, and thus may be functionally silent at resting membrane potentials. LTP converts silent synapses to functional ones by causing the rapid appearance of AMPA currents. These observations suggest that thalamocortical synapses may be formed as silent synapses which are subsequently made functional by LTP. LTP and LTD may then regulate the efficacy of these functional synapses and thereby contribute to experience-dependent changes in S1 thalamocortical circuits.

Animals↗