Glutamate is the major excitatory neurotransmitter in cerebral cortex. Electrophysiology and pharmacology have distinguished several types of glutamate receptors, but only with the advent of modern molecular techniques has their full diversity been recognized. Given the central role of glutamate in excitatory neurotransmission, understanding its receptors is of fundamental significance to neuroscience. It may also have practical implications: Drugs acting on glutamergic systems have not yet had a major impact on clinical practice, presumably because the transmitter is so ubiquitous that the selectivity of these agents is limited. Rational design based on a better understanding of receptor subtypes may yield a new generation of drugs with greater specificity of action. Novel research on the synaptic localization of glutamate receptor subunits in dentate gyrus and somatic sensory cortex is proposed, utilizing a new postembedding gold immunocytochemical technique for electron microscopic localization. This will allow us to investigate the subcellular distribution of glutamate receptors and their relationship to the plasma membrane and the active zone, as well as to assess how faithfully light microscopy reflects the underlying distribution of receptors. To explore how the arrangement of glutamate receptors may influence calcium entry into neurons, we will study the pattern of colocalization of AMPA subunits, and the distribution of AMPA and NMDA receptors on spines and dendritic shafts. The information thus gathered will allow study of the dynamics of glutamate receptors. The third part of the proposed research will test whether there are changes in distribution, concentration, or expression of these receptors associated with altered synaptic efficacy in two models of cortical plasticity: responsiveness in the barrel field of somatic sensory cortex after modification of its input, and long-term potentiation in the perforant pathway from entorhinal cortex to dentate gyrus. A deeper knowledge of mechanisms that may underlie cortical plasticity is of potential significance in understanding the reorganization associated with recovery from brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029879-07
Application #
2685683
Study Section
Sensory Disorders and Language Study Section (CMS)
Program Officer
Broman, Sarah H
Project Start
1991-07-20
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Valtschanoff, J G; Weinberg, R J (2001) Laminar organization of the NMDA receptor complex within the postsynaptic density. J Neurosci 21:1211-7
Valtschanoff, J G; Burette, A; Davare, M A et al. (2000) SAP97 concentrates at the postsynaptic density in cerebral cortex. Eur J Neurosci 12:3605-14
Naisbitt, S; Valtschanoff, J; Allison, D W et al. (2000) Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein. J Neurosci 20:4524-34
Naisbitt, S; Kim, E; Tu, J C et al. (1999) Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23:569-82
Valtschanoff, J G; Burette, A; Wenthold, R J et al. (1999) Expression of NR2 receptor subunit in rat somatic sensory cortex: synaptic distribution and colocalization with NR1 and PSD-95. J Comp Neurol 410:599-611
Kharazia, V N; Weinberg, R J (1999) Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. J Comp Neurol 412:292-302
Conti, F; Weinberg, R J (1999) Shaping excitation at glutamatergic synapses. Trends Neurosci 22:451-8
Wyszynski, M; Kharazia, V; Shanghvi, R et al. (1998) Differential regional expression and ultrastructural localization of alpha-actinin-2, a putative NMDA receptor-anchoring protein, in rat brain. J Neurosci 18:1383-92
Desmond, N L; Weinberg, R J (1998) Enhanced expression of AMPA receptor protein at perforated axospinous synapses. Neuroreport 9:857-60
Niethammer, M; Valtschanoff, J G; Kapoor, T M et al. (1998) CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90. Neuron 20:693-707

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