Biomedical subjects

Mark F Bear

Publications and source records attributed to Mark F Bear.

At least 19 recordsLinked to original sources

PubMed2007

Deprivation-induced synaptic depression by distinct mechanisms in different layers of mouse visual cortex.

Long-term depression (LTD) induced by low-frequency synaptic stimulation (LFS) was originally introduced as a model to probe potential mechanisms of deprivation-induced synaptic depression in visual cortex. In hippocampus, LTD requires activation of postsynaptic NMDA receptors, PKA, and the clathrin-dependent endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. It has long been assumed that LTD induced in visual cortical layer 2/3 by LFS of layer 4 uses similar mechanisms. Here we show in mouse visual cortex that this conclusion requires revision. We find that LTD induced in layer 2/3 by LFS is unaffected by inhibitors of PKA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis but is reliably blocked by an endocannabinoid CB1 receptor antagonist. Conversely, LFS applied to synapses on layer 4 neurons produces LTD that appears mechanistically identical to that in CA1 and is insensitive to CB1 blockers. Occlusion experiments suggest that both mechanisms contribute to the loss of visual responsiveness after monocular deprivation.

Animals↗

PubMed2006

Learning induces long-term potentiation in the hippocampus.

Years of intensive investigation have yielded a sophisticated understanding of long-term potentiation (LTP) induced in hippocampal area CA1 by high-frequency stimulation (HFS). These efforts have been motivated by the belief that similar synaptic modifications occur during memory formation, but it has never been shown that learning actually induces LTP in CA1. We found that one-trial inhibitory avoidance learning in rats produced the same changes in hippocampal glutamate receptors as induction of LTP with HFS and caused a spatially restricted increase in the amplitude of evoked synaptic transmission in CA1 in vivo. Because the learning-induced synaptic potentiation occluded HFS-induced LTP, we conclude that inhibitory avoidance training induces LTP in CA1.

Animals↗

PubMed2006

Activity-dependent regulation of NR2B translation contributes to metaplasticity in mouse visual cortex.

Visual experience and deprivation bidirectionally modify the NR2A and NR2B subunit composition of NMDARs, and these changes in turn modify the properties of synaptic plasticity in the visual cortex. Deprivation-induced lowering of the NR2A/2B ratio can occur by altering either NR2A or NR2B protein levels, but how a reduction in synaptic activity regulates these changes in a subunit-specific manner is poorly understood. Here, we find that visual deprivation in juvenile mice by dark-rearing or monocular lid suture reduces the NR2A/2B ratio in the deprived cortex in temporally distinct phases--initially by increasing NR2B protein levels, and later by decreasing NR2A protein levels. Brief dark-exposure of juvenile rats likewise produces an increase in NR2B expression. Furthermore, we are able to model the early increase in NR2B by blocking NMDARs in vitro, and we find that translation of NR2B is likely a major point of regulation. Translation of NR2A is not regulated in this manner. Therefore, the differential translational regulation of NR2A and NR2B may contribute to experience-dependent modification of NMDAR subunit composition.

Amaurosis Fugax↗

PubMed2006

Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression.

The triggering of both NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus requires a rise in postsynaptic calcium. A prominent hypothesis has been that the detailed properties of this postsynaptic calcium signal dictate whether LTP or LTD is generated by a given pattern of synaptic activity. Recently, however, evidence has been presented that the subunit composition of the NMDA receptor (NMDAR) determines whether a synapse undergoes LTP or LTD with NR2A-containing NMDARs triggering LTP and NR2B-containing NMDARs triggering LTD. In the present study, the role of NR2B-containing synaptic NMDARs in the induction of LTD in CA1 pyramidal cells has been studied using the selective NR2B antagonists, ifenprodil and Ro25-6981. While both antagonists reduced NMDAR-mediated synaptic currents, neither prevented induction of LTD. These results demonstrate that activation of NR2B-containing NMDARs is not an absolute requirement for the induction of LTD in the hippocampus.

Animals↗

PubMed2006

Instructive effect of visual experience in mouse visual cortex.

We describe a form of experience-dependent response enhancement in the visual cortex of awake mice. Repeated presentations of grating stimuli of a single orientation result in a persistent enhancement of responses evoked by the test stimulus. Response potentiation is specific to the orientation of the test stimulus, develops gradually over the course of several training sessions, and occurs in both juvenile and adult mice. The stimulus-selective response potentiation (SRP) can mask deprivation-induced response depression in adult mice. SRP requires NMDA receptor activation and is prevented by viral delivery of a peptide that interferes with AMPA receptor trafficking. SRP may reveal the mechanisms involved in certain forms of perceptual learning.

Animals↗

PubMed2006

Bidirectional modifications of visual acuity induced by monocular deprivation in juvenile and adult rats.

Recent electrophysiological studies of rodent visual cortex suggest that, in addition to deprived-eye depression, monocular deprivation (MD) also shifts ocular dominance by potentiation of open-eye responses. We used computer-based, two-choice discrimination tasks to assess the behavioral significance of these findings in rats. As expected, prolonged MD, from postnatal day 21 until adulthood (>150 d) markedly decreased visual acuity through the deprived eye. However, we also found that the acuity through the nondeprived eye was significantly enhanced compared with normally reared controls. Interestingly, when the deprived eye was opened in adults, there was a gradual but incomplete recovery of acuity in the deprived eye preceded by a loss of the enhanced acuity in the nondeprived eye. These changes were reversed by again reclosing the eye. These findings suggest that the bidirectional changes in visually evoked responses after MD are behaviorally meaningful and that significant plasticity is exhibited well into adulthood.

Age Factors↗

PubMed2006

Reward timing in the primary visual cortex.

We discovered that when adult rats experience an association between visual stimuli and subsequent rewards, the responses of a substantial fraction of neurons in the primary visual cortex evolve from those that relate solely to the physical attributes of the stimuli to those that accurately predict the timing of reward. In addition to revealing a remarkable type of response plasticity in adult V1, these data demonstrate that reward-timing activity-a "higher" brain function-can occur very early in sensory-processing paths. These findings challenge the traditional interpretation of activity in the primary visual cortex.

Action Potentials↗

PubMed2006

Stimulus for rapid ocular dominance plasticity in visual cortex.

Although it has been known for decades that monocular deprivation shifts ocular dominance in kitten striate cortex, uncertainty persists about the adequate stimulus for deprivation-induced losses of cortical responsiveness. In the current study we compared the effects of 2 days of lid closure and 2 days of monocular blur using an overcorrecting contact lens. Our finding of comparable ocular dominance shifts in visual cortex indicates that deprived-eye response depression is not a result of reduced retinal illumination. The quality rather than the quantity of retinal illumination is the key factor for ocular dominance plasticity. These data have implications for both the mechanism and treatment of amblyopia.

Action Potentials↗

PubMed2005

Courting a cure for fragile X.

Fragile X syndrome is the most common heritable cause of mental retardation. Previous work has suggested that overactive signaling by group I metabotropic glutamate receptors (mGluRs) may be a mechanism underlying many of the disease symptoms. As a test of this theory, McBride et al. show that in a Drosophila model for Fragile X syndrome, treatment with mGluR antagonists can rescue short-term memory, courtship, and mushroom body defects.

Animals↗

PubMed2005

Role for A kinase-anchoring proteins (AKAPS) in glutamate receptor trafficking and long term synaptic depression.

Expression of N-methyl d-aspartate (NMDA) receptor-dependent homosynaptic long term depression at synapses in the hippocampus and neocortex requires the persistent dephosphorylation of postsynaptic protein kinase A substrates. An attractive mechanism for expression of long term depression is the loss of surface AMPA (alpha-amino-3-hydroxy-5-methylisoxazale-4-propionate) receptors at synapses. Here we show that a threshold level of NMDA receptor activation must be exceeded to trigger a stable loss of AMPA receptors from the surface of cultured hippocampal neurons. NMDA also causes displacement of protein kinase A from the synapse, and inhibiting protein kinase A (PKA) activity mimics the NMDA-induced loss of surface AMPA receptors. PKA is targeted to the synapse by an interaction with the A kinase-anchoring protein, AKAP79/150. Disruption of the PKA-AKAP interaction is sufficient to cause a long-lasting reduction in synaptic AMPA receptors in cultured neurons. In addition, we demonstrate in hippocampal slices that displacement of PKA from AKADs occludes synaptically induced long term depression. These data indicate that synaptic anchoring of PKA through association with AKAPs plays an important role in the regulation of AMPA receptor surface expression and synaptic plasticity.

Adaptor Proteins, Signal Transducing↗

PubMed2004

How monocular deprivation shifts ocular dominance in visual cortex of young mice.

We used a chronic recording method to document the kinetics of ocular dominance (OD) plasticity induced by temporary lid closure in young mice. We find that monocular deprivation (MD) induces two separate modifications: (1) rapid, deprivation-induced response depression and (2) delayed, deprivation-enabled, experience-dependent response potentiation. To gain insight into how altering retinal activity triggers these cortical responses, we compared the effects of MD by lid closure with monocular inactivation (MI) by intravitreal injection of tetrodotoxin. We find that MI fails to induce deprived-eye response depression but promotes potentiation of responses driven by the normal eye. These effects of MI in juvenile mice closely resemble the effects of MD in adult mice. Understanding how MI and MD differentially affect activity in the visual system of young mice may provide key insight into how the critical period ends.

Age Factors↗

PubMed2004

LTP and LTD: an embarrassment of riches.

LTP and LTD, the long-term potentiation and depression of excitatory synaptic transmission, are widespread phenomena expressed at possibly every excitatory synapse in the mammalian brain. It is now clear that "LTP" and "LTD" are not unitary phenomena. Their mechanisms vary depending on the synapses and circuits in which they operate. Here we review those forms of LTP and LTD for which mechanisms have been most firmly established. Examples are provided that show how these mechanisms can contribute to experience-dependent modifications of brain function.

Animals↗

PubMed2004

A morphological correlate of synaptic scaling in visual cortex.

We studied the response of dendritic spines in the thalamic-recipient zone of rat visual cortex to simple manipulations of the visual environment. We measured the morphologies of a total of 3824 spines located on the basal dendrites of 60 layer 3 pyramidal cells. As expected from previous studies, we found a significantly lower spine density in dark-reared animals at postnatal day 30 (P30) compared with light-reared controls. Additional analysis revealed that the spines in dark-reared animals were significantly shorter and more bulbous than in light-reared animals. When these two results were combined, we found that the total synaptic area per unit length of dendrite was conserved, compatible with the phenomenon of "synaptic scaling." We also found that the increase in average spine head diameter is reversed by 10 d of light exposure (starting at P20), but surprisingly, the decrease in spine density is not. Thus, not all effects of dark rearing can be reversed by subsequent visual experience, even when the experience occurs during the third postnatal week.

Animals↗

PubMed2004

Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1.

Activation of group 1 metabotropic glutamate receptors (mGluRs) induces long-term depression (LTD) of synaptic transmission that relies on dendritic protein synthesis. We investigated the signal transduction pathways required for mGluR-LTD to identify candidate mechanisms for mGluR regulation of synaptic protein synthesis. Our results demonstrate a role for extracellular signal-regulated protein kinase (ERK), a subclass of the mitogen-activated protein kinases (MAPKs), in mGluR-LTD in area CA1 of the rat hippocampus. Inhibitors of the upstream kinase of ERK, MAP/ERK kinase significantly reduce mGluR-LTD induced by the group 1 agonist dihydroxyphenylglycine (DHPG) and synaptic stimulation but do not affect NMDA receptor-dependent LTD. In contrast, inhibitors of p38 MAPK were ineffective against DHPG-induced LTD. Consistent with the role of ERK in mGluR-LTD, we observed that DHPG treatment of hippocampal slices (isolated CA1), at concentrations that induce LTD, results in a robust phosphorylation of ERK but not of p38 MAPK. These results point to ERK as an important regulator of mGluR-LTD and a potential mechanism for mGluR regulation of synaptic protein synthesis.

Animals↗

PubMed2004

Significance of N-methyl-D-aspartate (NMDA) receptor-mediated signaling in human keratinocytes.

Increasing data suggest that glutamate might act as a cell-signaling molecule in non-neuronal tissues such as the skin. Here we demonstrate the presence of functional N-methyl-D-aspartate (NMDA)-type glutamate receptors in human keratinocytes. NMDA receptor expression strongly reflects the degree of cell-to-cell contact. Wounding polarizes the expression of NMDA receptors in keratinocytes involved in re-epithelialization, and the process of re-epithelialization is inhibited by NMDA receptor activation. We also demonstrate that squamous cell carcinomas lack NMDA receptors. Our data suggest that Ca2+ entry through NMDA receptors influences the cycle of keratinocyte proliferation, differentiation, and migration during epithelialization. Moreover, NMDA receptor activation might play a role in contact-mediated inhibition of growth, a process that is absent during neoplastic pathology. This receptor may serve as a pharmacological target for modulating keratinocyte behavior and treating cutaneous disorders.

Aniline Compounds↗

PubMed2004

The mGluR theory of fragile X mental retardation.

Many of the diverse functional consequences of activating group 1 metabotropic glutamate receptors require translation of pre-existing mRNA near synapses. One of these consequences is long-term depression (LTD) of transmission at hippocampal synapses. Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus. This finding is consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs. Here we present a theory that can account for diverse neurological and psychiatric aspects of fragile X syndrome, based on the assumption that many of the protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome. The theory suggests new directions for basic research as well as novel therapeutic approaches for the treatment of humans with fragile X, the most frequent inherited cause of mental retardation and an identified cause of autism.

Animals↗

PubMed2003

Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.

PSD-95 is a major scaffolding protein of the postsynaptic density, tethering NMDA- and AMPA-type glutamate receptors to signaling proteins and the neuronal cytoskeleton. Here we show that PSD-95 is regulated by the ubiquitin-proteasome pathway. PSD-95 interacts with and is ubiquitinated by the E3 ligase Mdm2. In response to NMDA receptor activation, PSD-95 is ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that block PSD-95 ubiquitination prevent NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevent NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. This is consistent with the notion that PSD-95 levels are an important determinant of AMPA receptor number at the synapse. These data suggest that ubiquitination of PSD-95 through an Mdm2-mediated pathway is critical in regulating AMPA receptor surface expression during synaptic plasticity.

Acetylcysteine↗

PubMed2003

Evidence for altered NMDA receptor function as a basis for metaplasticity in visual cortex.

Sensory deprivation alters the properties of synaptic plasticity induced in the superficial layers of the visual cortex, facilitating long-term potentiation and reducing long-term depression (LTD) across a range of stimulation frequencies. Available data are compatible with either a downregulation of the mechanisms of LTD or an upregulation of NMDA receptor function in the visual cortex of dark-reared animals. Here, we provide evidence for enhanced NMDA receptor function by showing that deprivation produces a horizontal shift in the frequency-response function, decreasing LTD in response to 1 Hz stimulation, but increasing LTD in response to 0.5 Hz stimulation. In addition, we show that the effects of dark-rearing on the frequency dependence of LTD can be reversed acutely by partial NMDA receptor blockade. Finally, we show that an in vivo manipulation that rapidly downregulates NMDA receptor function in the visual cortex, brief light exposure, also rapidly reverses the effect of dark-rearing on LTD.

Animals↗