MAPPING THE GENES FOR NEUROLEPTIC RESPONSE

Oregon Health And Science University, Portland OR

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Abstract

DESCRIPTION (Adapted from applicant's abstract): The following application is a request for continued support of MH51372 "Mapping the Genes for Neuroleptic Response." The original application addressed the question of "what genes contribute to the variability of neuroleptic-induced extrapyramidal symptoms (EPS)?" As noted in Section C, we have been able to demonstrate that the catalepsy response maps to likely candidate genes: Drd2, Htr1b, Chat and Htr2a. We are now requesting support to move MH51372 in new directions. The phenotype at the center of the current application is prepulse inhibition (PPI) of the acoustic startle response (ASR). Schizophrenics show marked deficits in PPI and other sensory gating mechanisms which are at least partially reversed by both typical and atypical neuroleptics. Thus, our focus now is on how genes regulate the neuroleptic-responsive behaviors which are abnormal in schizophrenia. The goal of the application is to map the major QTLs for PPI to a resolution of 1 cM. The specific aims may be summarized: 1 To conduct a genome wide search for QTLs associated with PPI of ASR in C57BL/6J (B6) x DBA/2J (D2) F2 individuals. The focus on B6D2 genotypes is justified a) because the parental strains are highly polymorphic (Dietrich et al. 1992;1996) and b) because of the marked differences in PPI between the strains (Bullock et al. 1995; Logue et al. 1997; McCaughran et al. 1997). To expand the search for prepulse inhibition QTLs, we propose 2. To conduct a genome wide QTL search in a BALB/cJ (C) x LP/J (LP) F2 cross. The CLP F2 cross was chosen because the parental strains are highly polymorphic between themselves and the B6 and D2 strains (Dietrich et at. 1992) and because the parental strains are at the extremes of the distribution among common inbred mouse strains for several phenotypes (e.g. D2 dopamine receptor density; Kanes et al. 1993) which are likely to influence PPI. In addition, the C and LP strains differ significantly in PPI. For the QTLs detected in specific aims 1 and 2, we propose - 3. To construct a series of "interval specific congenic strains(ISCS)" which enables mapping the QTL into a 1 cM interval. Paralleling the work of specific aims 1-3, we propose - 4. To continue the characterization of the PPI phenotype. Two general areas will be investigated: One - To what extent do deficits in PPI extend to other measures of sensory gating or attentional function, e.g., latent inhibition? Two - Do deficits in PPI show a similar response to typical and atypical neuroleptics across genotypes? Overall, the data obtained should be an important first step towards understanding the genetic regulation of behaviors known to be abnormal in schizophrenia and related disorders.