Derangements in synaptic transmission are an important part of the pathology of several neurological and mental diseases including epilepsy, schizophrenia, depression and perhaps Alzheimer's disease. Despite the medical significance of synaptic transmission and the important roles of synapses in information processing and storage in the brain, relatively little is known about the molecular mechanisms underlying regulation of synaptic transmission. The proposed research involves a study of the molecular structures of synapses in the central nervous system (CNS). It focuses on the identification and study of proteins associated with the postsynaptic density (PSD) a large fibrous specialization of the submembrane cytoskeleton that adheres to the postsynaptic membrane opposite presynaptic terminals. PSDs are especially prominent in glutamatergic terminals in the CNS where they are believed to function as anchoring sites for synaptic receptors and signal transduction molecules as well as for molecules mediating adhesion between the pre and postsynaptic membranes. The applicants have applied modern cell biological and microchemical methods to sequence and characterized several proteins associated with the PSD, including NR2B, a subunit of the NMDA receptors, PSD-95, an apparent clustering and adapter molecule, and densin-180, an apparent new adhesion molecule. Here they propose to extend their studies by completing the characterization of two additional PSD proteins that we have sequenced, by beginning to study the association among the PSD proteins that mediate assembly and function of the PSD, and by using recombinant DNA methodology to test hypothesis about the specific functions of PSD proteins in the synapse.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028710-11
Application #
6187247
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Heemskerk, Jill E
Project Start
1997-08-01
Project End
2001-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
11
Fiscal Year
2000
Total Cost
$258,294
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Kennedy, Mary B (2017) Biochemistry and neuroscience: the twain need to meet. Curr Opin Neurobiol 43:79-86
Wang, Shiyi; Stanika, Ruslan I; Wang, Xiaohan et al. (2017) Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Cav1.2 Ca2+ Channels at Excitatory Synapses. J Neurosci 37:4679-4691
Muhia, Mary; Willadt, Silvia; Yee, Benjamin K et al. (2012) Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout. Learn Mem 19:268-81
Carlisle, Holly J; Luong, Tinh N; Medina-Marino, Andrew et al. (2011) Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction. J Neurosci 31:16194-207
Marcora, Edoardo; Kennedy, Mary B (2010) The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-ýýB from the synapse to the nucleus. Hum Mol Genet 19:4373-84
Knuesel, Irene; Elliott, Abigail; Chen, Hong-Jung et al. (2005) A role for synGAP in regulating neuronal apoptosis. Eur J Neurosci 21:611-21
Carlisle, Holly J; Kennedy, Mary B (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182-7
Vazquez, Luis E; Chen, Hong-Jung; Sokolova, Irina et al. (2004) SynGAP regulates spine formation. J Neurosci 24:8862-72
Oh, Jeong S; Manzerra, Pasquale; Kennedy, Mary B (2004) Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 279:17980-8
Moon, I S; Park, I S; Schenker, L T et al. (2001) Presence of both constitutive and inducible forms of heat shock protein 70 in the cerebral cortex and hippocampal synapses. Cereb Cortex 11:238-48

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