Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats

Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague-Dawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia. After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH). Startle and PPI were assessed in SD and LE rats administered d-amphetamine (0 vs. 4.5 mg/kg, sc). Two weeks later, brain tissue was processed for comt, nrg1, grid2, and csnk1e expression; blood comt expression was also tested. Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE > SD expression in most genes and regions, and female > male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120 ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30 ms PPI and startle magnitude correlated significantly with VH nrg1 and blood comt expression. Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia.