The effects of the proline dehydrogenase and the reticulon-4 receptor genes in the development of schizophrenia

Schizophrenia is an etiologically complex and includes multiple genetic and environmental risk factors. The methodology used when assessing human participants results in correlational and sometimes inconsistent data. Animal models permit an understanding of both causal mechanistic and etiological events that are relevant to the development of schizophrenia. In the present dissertation, the Proline Dehydrogenase (PRODH) and the Reticulon-4 Receptor (RTN4R) genes were mutated in the mouse to determine their impact on the development of schizophrenia.;RTN4R is involved in limiting axonal sprouting and neural plasticity by inhibiting the outgrowth ofneurites. Two novel Rtn4r mutant strains with distinct point mutations in the functional area of the receptor, were characterized for the aforementioned endophenotypes. Male mutant mice (n=6-7) of the M2-1836 strain (G566A; Arg189His substitution; 97% C57BL/6J x 3% DBA/2J background) exhibited enhanced social preference, reflecting a decreased anxiety response, and impaired spatial cognition, but no other impairments, relative to wildtype littermates (n=7-9). Male mutant mice (n=14-15) of the M2-1841 strain (G767T; Arg256Leu substitution; 97% C57BL/6J x 3% C3H/HeJ background) exhibited a decreased startle reflex and a non-significant trend for a deficit in PPI, but did not exhibit any other impairments, relative to wildtype littermates (n=9).;The results suggest that mutations in Prodh and Rtn4r may have a causal role in the development of some schizophrenia-related endophenotypes, and may therefore be causally linked to the development of schizophrenia.;KEYWORDS: schizophrenia; mouse model; proline dehydrogenase; reticulon-4 receptor, prepulse inhibition; social interaction; spatial cognition; paddle pool; glutamate; neurodevelopment.;PRODH is involved in the degradation of L-proline, and glutamatergic potentiation and reuptake, and is considered to be an important positional and functional candidate gene. Male Prodh (97% C57BL/6J x 3% 129/ReJ background) mutant (n=37-44) and wildtype (n=13-16) littermates were tested for schizophrenia related endophenotypes, including sensorimotor gating deficits, using the prepulse inhibition of the acoustic startle response (PPI) task, locomotor hyperactivity, social interaction deficits, and deficits in spatial cognition using a paddle pool task. The results indicate that Prodh mutant mice exhibit decreased social interaction and impaired spatial cognition. There were no deficits in startle, PPI or locomotor activity. Administration of clozapine, an atypical antipsychotic drug, reversed the social interaction impairment.