Altered netrin‐1 receptor expression in dopamine terminal regions following neonatal ventral hippocampal lesions in the rat

Abstract

Neonatal ventral hippocampal (nVH) lesions in rats, which model certain features of schizophrenia, alter dopamine (DA)-mediated behaviors in adulthood. The precise mechanisms underlying these effects remain elusive; however, neuronal reorganization within the medial prefrontal cortex (mPFC) has been suggested. Netrins are developmental cues that organize brain wiring, including the mesocorticolimbic DA circuitry. We showed recently that the netrin-1 receptors DCC and UNC5H are highly expressed by DA neurons and that variation in DCC levels during development lead to profound changes in mesocorticolimbic DA function and behavior in adulthood. We hypothesized that changes in netrin-1 receptor function could be one of the mechanisms producing enduring changes in DA function in nVH-lesioned animals. To begin to explore this idea, we examined the effects of nVH lesions on DCC and UNC5H expression in brain regions receiving robust DA innervation; the mPFC, striatum, and nucleus accumbens (NAcc) at three developmental time points; 3 days after lesion, before puberty and during early adulthood. Expression was also examined in the cerebellar simple lobule; a brain region deprived of DA innervation. Neonatal VH lesions produced dynamic changes in DCC expression in the mPFC and NAcc. The direction and magnitude of these changes depended on the developmental age and brain region examined and were specific to regions receiving DA innervation. Although further studies are required to understand the functional significance of these changes, these results raise the interesting possibility that nVH lesions, and perinatal insults in general, may exert their neuronal reorganizational effects by modulating netrin-1 function.