Disruption of synaptic function has been implicated in a number of developmental disorders. Synapses are highly specialized dynamic structures, sites of presynaptic neurotransmitter release and postsynaptic responses. Several classes of molecules including kinases have been implicated in these processes, but additional studies are necessary to elucidate the complex series of events that result in normally functioning synapses. PSD-95 is a postsynaptic density protein that clusters K+ ion channels and NMDA receptors at synapses. The N-terminal domain of PSD-95 mediates its multimerization and is critical for channel clustering. This domain is phosphorylated by the p35-cdk5 kinase. Mice lacking p35 have an increased susceptibility to seizures and a diminished ability to recover from them compared to wild type. Preliminary studies revealed that p35-cdk5 kinase is present in the postsynaptic density fraction and that p35 null mice have abnormal aggregations of synaptic proteins. Furthermore, the p35-cdk5 kinase can phosphorylate PSD-95. Remarkably, phosphorylation by p35-cdk5 prevents the clustering of Shaker-type K+ channels by PSD-95 in heterologous cells. These findings strongly implicate the p35-cdk5 kinase in the regulation of synaptic assembly, stability and function. In addition, they have led to the hypothesis that the phosphorylation of PSD-95 by the p35-cdk5 kinase prevents the multimerization of PSD-95 which, consequently, affects the clustering of K+ channels and NMDA receptors. According to this hypothesis, p35-cdk5 plays an integral role in synaptic function by regulating the assembly of postsynaptic structures and thus allowing rapid alterations in their electrical/biochemical properties. The proposed studies aim to establish the function of p35-cdk5 regulation in the clustering of the receptor and the assembly of synaptic structures. They will certainly allow significant advancement in the understanding of structural plasticity of synapses and their malfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH062161-02
Application #
6392871
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (01))
Program Officer
Asanuma, Chiiko
Project Start
2000-07-14
Project End
2002-08-31
Budget Start
2001-07-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$86,000
Indirect Cost
Name
Harvard University
Department
Pathology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115