This Project contributes to our understanding of the role played by intracellular signaling cascades in regulating the brain's striatal and related limbic circuits under normal circumstances and in animal models of schizophrenia and antipsychotic drug action in two main ways. First, the Project will use a broad battery of behavioral tests relevant to schizophrenia and antipsychotic drug action to gain novel insight, at the systems level, into the normal and pathophysiological functioning of DARPP-32, spinpphilin, RCS, and related intracellular signaling pathways in brain. In this way, the Project will provide a critical level of analysis that complements and integrates the molecular and cellular investigations of the other Projects. VVe will analyze the rich array of mutant mice generated by this Center, focusing initially on mice with point mutations in the various phosphorylation sites of DARPP-32, as well as mice lacking DARPP-32, spinophilin, or RCS in specific neuronal cell types. Moreover, we will analyze mice with highly localized knockouts of these various proteins in subregions of striatum and frontal cortex. Such knockouts will be achieved by use of a viral-Cre recombinase method widely used in my laboratory. The imperative to employ a broad battery of behavioral tests is that it is difficult to infer something about complex behavior from a single test or even a limited number of tests. Second, the Project will extend the studies of DARPP-32, spinophilin, RCS, and related signaling pathways to the neuronal nucleus by establishing the influence of these pathways on two major transcription factors, CREB and ?FosB, in striatal and frontal cortical neurons. Thus, in addition to regulating synaptic transmission in the short-term, DARPP-32 is a critical control point that regulates the ability of synaptic stimuli to alter gene transcription in target neurons and thereby influence the functioning of neural circuits over the longer-term. We have demonstrated that DARPP-32 controls the induction in striatum of CREB (cAMP response element binding protein) and ?FosB (a Fos family protein), which are known to play crucial roles in the regulation of striatal and cortical function. Both transcription factors are induced by antipsychotic drugs in these regions in a DARPP-32 dependent manner. Analysis of CREB- and ?FosB-mediated transcription in the various types of DARPP-32, spinophilin, RCS, and related mutant mice described above will complement molecular and cellular studies underway in the other Projects of this Center, and help provide an increasingly more complete understanding of the mechanism of action of antipsychotic drugs in the brain and the pathophysiology of schizophrenia in animal models.
Showing the most recent 10 out of 56 publications
