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Biomedical subjects

M F Bear

Publications and source records attributed to M F Bear.

At least 19 recordsLinked to original sources
PubMed2005

Therapeutic implications of the mGluR theory of fragile X mental retardation.

Evidence is reviewed that the consequences of group 1 metabotropic glutamate receptor (Gp1 mGluR) activation are exaggerated in the absence of the fragile X mental retardation protein, likely reflecting altered dendritic protein synthesis. Abnormal mGluR signaling could be responsible for remarkably diverse psychiatric and neurological symptoms in fragile X syndrome, including delayed cognitive development, seizures, anxiety, movement disorders and obesity.

Animals↗
PubMed2001

A role for the cytoplasmic polyadenylation element in NMDA receptor-regulated mRNA translation in neurons.

The ability of neurons to modify synaptic connections based on activity is essential for information processing and storage in the brain. The induction of long-lasting changes in synaptic strength requires new protein synthesis and is often mediated by NMDA-type glutamate receptors (NMDARs). We used a dark-rearing paradigm to examine mRNA translational regulation in the visual cortex after visual experience-induced synaptic plasticity. In this model system, we demonstrate that visual experience induces the translation of mRNA encoding the alpha-subunit of calcium/calmodulin-dependent kinase II in the visual cortex. Furthermore, this increase in translation is NMDAR dependent. One potential source for newly synthesized proteins is the translational activation of dormant cytoplasmic mRNAs. To examine this possibility, we developed a culture-based assay system to study translational regulation in neurons. Cultured hippocampal neurons were transfected with constructs encoding green fluorescent protein (GFP). At 6 hr after transfection, approximately 35% of the transfected neurons (as determined by in situ hybridization) expressed detectable GFP protein. Glutamate stimulation of the cultures at this time induced an increase in the number of neurons expressing GFP protein that was NMDAR dependent. Importantly, the glutamate-induced increase was only detected when the 3'-untranslated region of the GFP constructs contained intact cytoplasmic polyadenylation elements (CPEs). Together, these findings define a molecular mechanism for activity-dependent synaptic plasticity that is mediated by the NMDA receptor and requires the CPE-dependent translation of an identified mRNA.

3' Untranslated Regions↗
PubMed2001

Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo.

It has been suggested that NMDA receptor-dependent synaptic strengthening, like that observed after long-term potentiation (LTP), is a mechanism by which experience modifies responses in the neocortex. We report here that patterned (theta burst) stimulation of the dorsal lateral geniculate nucleus reliably induces LTP of field potentials (FPs) evoked in primary visual cortex (Oc1) of adult rats in vivo. The response enhancement is saturable, long-lasting, and dependent on NMDA receptor activation. To determine the laminar locus of these changes, current source density (CSD) analysis was performed on FP profiles obtained before and after LTP induction. LTP was accompanied by an enhancement of synaptic current sinks located in thalamorecipient (layer IV and deep layer III) and supragranular (layers II/III) cell layers. We also examined immunocytochemical labeling for the immediate early gene zif-268 1 hr after induction of LTP. In concert with the laminar changes observed in CSD analyses, we observed a significant increase in the number of zif-268-immunopositive neurons in layers II-IV that occurred over a wide extent of Oc1. Last, we investigated the functional consequences of LTP induction by monitoring changes in visually evoked potentials. After LTP, we observed that the cortical response to a full-field flash was significantly enhanced and that responses to grating stimuli were increased across a range of spatial frequencies. These findings are consistent with growing evidence that primary sensory cortex remains plastic into adulthood, and they show that the mechanisms of LTP can contribute to this plasticity.

Animals↗
PubMed2001

Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory.

Calcineurin is a calcium-dependent protein phosphatase that has been implicated in various aspects of synaptic plasticity. By using conditional gene-targeting techniques, we created mice in which calcineurin activity is disrupted specifically in the adult forebrain. At hippocampal Schaffer collateral-CA1 synapses, LTD was significantly diminished, and there was a significant shift in the LTD/LTP modification threshold in mutant mice. Strikingly, although performance was normal in hippocampus-dependent reference memory tasks, including contextual fear conditioning and the Morris water maze, the mutant mice were impaired in hippocampus-dependent working and episodic-like memory tasks, including the delayed matching-to-place task and the radial maze task. Our results define a critical role for calcineurin in bidirectional synaptic plasticity and suggest a novel mechanistic distinction between working/episodic-like memory and reference memory.

Animals↗
PubMed2001

Developmental inhibitory gate controls the relay of activity to the superficial layers of the visual cortex.

A developmental reduction in the radial transmission of synaptic activity has been proposed to underlie the end of the critical period for experience-dependent modification in layers II/III of the visual cortex. Using paired-pulse stimulation, we investigated in visual cortical slices how the propagation of synaptic activity to the superficial layers changes during development and how this process is affected by sensory experience. The results can be summarized as follows. (1) Layers II/III responses to repetitive stimulation of the white matter become increasingly depressed between the third and sixth week of postnatal development, a time course that parallels the end of the critical period. (2) Paired-pulse depression is reduced after dark rearing and also by blocking inhibitory synaptic transmission. (3) Paired-pulse depression and its regulation by age and sensory experience is more pronounced when stimulation is applied to the white matter than when applied to layer IV. Together, these results are consistent with the idea that the maturation of intracortical inhibition reduces the capability of the cortex to relay incoming high-frequency patterns of activity to the supragranular layers.

Aging↗
PubMed2001

Heterosynaptic metaplasticity in the hippocampus in vivo: a BCM-like modifiable threshold for LTP.

The homeostatic maintenance of the "modification threshold" for inducing long-term potentiation (LTP) is a fundamental feature of the Bienenstock, Cooper, and Munro (BCM) model of synaptic plasticity. In the present study, two key features of the modification threshold, its heterosynaptic expression and its regulation by postsynaptic neural activity, were tested experimentally in the dentate gyrus of awake, freely moving rats. Conditioning stimulation ranging from 10 to 1,440 brief 400-Hz trains, when applied to medial perforant path afferents, raised the threshold for LTP induction heterosynaptically in the neighboring lateral perforant path synapses. This effect recovered slowly over a 7- to 35-day period. The same conditioning paradigms, however, did not affect the reversal of long-term depression. The inhibition of LTP by medial-path conditioning stimulation was N-methyl-D-aspartate (NMDA) receptor-dependent, but antidromic stimulation of the granule cells could also inhibit lateral path LTP induction, independently of NMDA receptor activation. Increased calcium buffering is a potential mechanism underlying the altered LTP threshold, but the levels of two important calcium-binding proteins did not increase after conditioning stimulation, nor was de novo protein synthesis required for generating the threshold shift. These data confirm, in an in vivo model, two key postulates of the BCM model regarding the LTP threshold. They also provide further evidence for the broad sensitivity of synaptic plasticity mechanisms to the history of prior activity, i.e., metaplasticity.

Animals↗
PubMed2001

Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in visual cortex.

The NMDA receptor (NMDAR) is a heteromer comprised of NR1 and NR2 subunits. Mice that overexpress the NR2B subunit exhibit enhanced hippocampal LTP, prolonged NMDAR currents, and improved memory ( Tang et al., 1999). In the current study, we explored visual cortex plasticity and NMDAR function in NR2B overexpressing transgenic mice. Unlike the hippocampus, in vitro synaptic plasticity of the visual cortex was unaltered by NR2B overexpression. Consistent with the plasticity findings, NMDAR excitatory postsynaptic current (EPSC) durations from layer 2/3 pyramidal cells were similar in wild-type (wt) and transgenic (tg) mice. Furthermore, temporal summation of NMDAR EPSCs to 10, 20, and 40 Hz stimulation did not differ between cells from wt and tg mice. Finally, although in situ studies clearly demonstrate overexpression of NR2B mRNA in visual cortex, we failed to observe a significant elevation in the synaptic expression of NR2B protein. We conclude that the synaptic ratio of NR2B over NR2A in the NMDA receptor complex in the visual cortex is not significantly influenced by the transgene overexpression. These data suggest that mRNA availability is not a limiting factor for the synthesis of NR2B protein in the visual cortex, and support the hypothesis that levels of NR2A, rather than NR2B, normally determine the subunit composition of NMDARs in visual cortex.

Animals↗
PubMed2001

Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex.

The receptive fields of visual cortical neurons are bidirectionally modified by sensory deprivation and experience, but the synaptic basis for these changes is unknown. Here we demonstrate bidirectional, experience-dependent regulation of the composition and function of synaptic NMDA receptors (NMDARs) in visual cortex layer 2/3 pyramidal cells of young rats. Visual experience decreases the proportion of NR2B-only receptors, shortens the duration of NMDAR-mediated synaptic currents, and reduces summation of synaptic NMDAR currents during bursts of high-frequency stimulation. Visual deprivation exerts an opposite effect. Although the effects of experience and deprivation are reversible, the rates of synaptic modification vary. Experience can induce a detectable change in synaptic transmission within hours, while deprivation-induced changes take days. We suggest that experience-dependent changes in NMDAR composition and function regulate the development of receptive field organization in visual cortex.

Animals↗
PubMed2001

Internalization of ionotropic glutamate receptors in response to mGluR activation.

Activation of group 1 metabotropic glutamate receptors (mGluRs) stimulates dendritic protein synthesis and long-term synaptic depression (LTD), but it remains unclear how these effects are related. Here we provide evidence that a consequence of mGluR activation in the hippocampus is the rapid loss of both AMPA and NMDA receptors from synapses. Like mGluR-LTD, the stable expression of this change requires protein synthesis. These data suggest that expression of mGluR-LTD is at least partly postsynaptic, and that a functional consequence of dendritic protein synthesis is the regulation of glutamate receptor trafficking.

Amino Acids↗
PubMed2001

Chemical induction of mGluR5- and protein synthesis--dependent long-term depression in hippocampal area CA1.

Recent work has demonstrated that specific patterns of synaptic stimulation can induce long-term depression (LTD) in area CA1 that depends on activation of metabotropic glutamate receptors (mGluRs) and rapid protein synthesis. Here we show that the same form of synaptic modification can be induced by brief application of the selective mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). DHPG-LTD 1) is a saturable form of synaptic plasticity, 2) requires mGluR5, 3) is mechanistically distinct from N-methyl-D-aspartate receptor (NMDAR)--dependent LTD, and 4) shares a common expression mechanism with protein synthesis-dependent LTD evoked using synaptic stimulation. DHPG-LTD should be useful for biochemical analysis of mGluR5- and protein synthesis-dependent synaptic modification.

2-Amino-5-phosphonovalerate↗
PubMed2000

Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity.

Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.

Animals↗
PubMed2000

Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.

A hippocampal pyramidal neuron receives more than 10(4) excitatory glutamatergic synapses. Many of these synapses contain the molecular machinery for messenger RNA translation, suggesting that the protein complement (and thus function) of each synapse can be regulated on the basis of activity. Here, local postsynaptic protein synthesis, triggered by synaptic activation of metabotropic glutamate receptors, was found to modify synaptic transmission within minutes.

Amino Acids↗
PubMed2000

Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo.

Experience-dependent regulation of synaptic strength has been suggested as a physiological mechanism by which memory storage occurs in the brain. Although modifications in postsynaptic glutamate receptor levels have long been hypothesized to be a molecular basis for long-lasting regulation of synaptic strength, direct evidence obtained in the intact brain has been lacking. Here we show that in the adult brain in vivo, synaptic glutamate receptor trafficking is bidirectionally, and reversibly, modified by NMDA receptor-dependent synaptic plasticity and that changes in glutamate receptor protein levels accurately predict changes in synaptic strength. These findings support the idea that memories can be encoded by the precise experience-dependent assignment of glutamate receptors to synapses in the brain.

Animals↗
PubMed1999

Bidirectional, experience-dependent regulation of N-methyl-D-aspartate receptor subunit composition in the rat visual cortex during postnatal development.

In the visual cortex, as elsewhere, N-methyl-D-aspartate receptors (NMDARs) play a critical role in triggering long-term, experience-dependent synaptic plasticity. Modifications of NMDAR subunit composition alter receptor function, and could have a large impact on the properties of synaptic plasticity. We have used immunoblot analysis to investigate the effects of age and visual experience on the expression of different NMDAR subunits in synaptoneurosomes prepared from rat visual cortices. NMDARs at birth are comprised of NR2B and NR1 subunits, and, over the first 5 postnatal weeks, there is a progressive inclusion of the NR2A subunit. Dark rearing from birth attenuates the developmental increase in NR2A. Levels of NR2A increase rapidly (in <2 hr) when dark-reared animals are exposed to light, and decrease gradually over the course of 3 to 4 days when animals are deprived of light. These data reveal that NMDAR subunit composition in the visual cortex is remarkably dynamic and bidirectionally regulated by sensory experience. We propose that NMDAR subunit regulation is a mechanism for experience-dependent modulation of synaptic plasticity in the visual cortex, and serves to maintain synaptic strength within an optimal dynamic range.

Animals↗
PubMed1999

BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex.

Maturation of the visual cortex is influenced by visual experience during an early postnatal period. The factors that regulate such a critical period remain unclear. We examined the maturation and plasticity of the visual cortex in transgenic mice in which the postnatal rise of brain-derived neurotrophic factor (BDNF) was accelerated. In these mice, the maturation of GABAergic innervation and inhibition was accelerated. Furthermore, the age-dependent decline of cortical long-term potentiation induced by white matter stimulation, a form of synaptic plasticity sensitive to cortical inhibition, occurred earlier. Finally, transgenic mice showed a precocious development of visual acuity and an earlier termination of the critical period for ocular dominance plasticity. We propose that BDNF promotes the maturation of cortical inhibition during early postnatal life, thereby regulating the critical period for visual cortical plasticity.

Age Factors↗
PubMed1999

Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine.

In a slice preparation of rat visual cortex, we discovered that paired-pulse stimulation (PPS) elicits a form of homosynaptic long-term depression (LTD) in the superficial layers when carbachol (CCh) or norepinephrine (NE) is applied concurrently. PPS by itself, or CCh and NE in the absence of synaptic stimulation, produced no lasting change. The LTD induced by PPS in the presence of NE or CCh is of comparable magnitude with that obtained with prolonged low-frequency stimulation (LFS) but requires far fewer stimulation pulses (40 vs 900). The cholinergic facilitation of LTD was blocked by atropine and pirenzepine, suggesting involvement of M1 receptors. The noradrenergic facilitation of LTD was blocked by urapidil and was mimicked by methoxamine, suggesting involvement of alpha1 receptors. beta receptor agonists and antagonists were without effect. Induction of LTD by PPS was inhibited by NMDA receptor blockers (completely in the case of NE; partially in the case of CCh), suggesting that one action of the modulators is to control the gain of NMDA receptor-dependent homosynaptic LTD in visual cortex. We propose that this is a mechanism by which cholinergic and noradrenergic inputs to the neocortex modulate naturally occurring receptive field plasticity.

Acetylcholine↗
PubMed1999

Monocular deprivation induces homosynaptic long-term depression in visual cortex.

Brief monocular deprivation during early postnatal development can lead to a depression of synaptic transmission that renders visual cortical neurons unresponsive to subsequent visual stimulation through the deprived eye. The Bienenstock-Cooper-Munro (BCM) theory proposes that homosynaptic mechanisms of long-term depression (LTD) account for the deprivation effects. Homosynaptic depression, by definition, occurs only at active synapses. Thus, in contrast to the commonly held view that the synaptic depression caused by monocular deprivation is simply a result of retinal inactivity, this theoretical framework indicates that the synaptic depression may actually be driven by the residual activity in the visually deprived retina. Here we examine the validity of this idea by comparing the consequences of brief monocular deprivation by lid suture with those of monocular inactivation by intra-ocular treatment with tetrodotoxin. Lid suture leaves the retina spontaneously active, whereas tetrodotoxin eliminates all activity. In agreement with the BCM theory, our results show that monocular lid suture causes a significantly greater depression of deprived-eye responses in kitten visual cortex than does treatment with tetrodotoxin. These findings have important implications for mechanisms of experience-dependent plasticity in the neocortex.

Animals↗