Modulation of Hippocampal Gamma Oscillations by Dopamine in Heterozygous Reeler Mice in vitro

The reelin haploinsufficient heterozygous reeler mice (HRM), an animal model of schizophrenia, have altered mesolimbic dopaminergic pathways and share similar neurochemical and behavioral properties with patients with schizophrenia. Dysfunctional neural circuitry with impaired gamma (gamma) oscillation (30-80 Hz) has been implicated in abnormal cognition in patients with schizophrenia. However, the function of neural circuitry in terms of gamma oscillation and its modulation by dopamine (DA) has not been reported in HRM. In this study, first, we recorded gamma oscillations in CA3 from wild-type mice (WTM) and HRM hippocampal slices, and we studied the effects of DA on gamma oscillations. We found that there was no difference in gamma power between WTM and HRM and that DA increased gamma power of WTM but not HRM, suggesting that DA modulations of network oscillations in HRM are impaired. Second, we found that N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 itself increased gamma power and occluded DA-mediated enhancement of gamma power in WTM but partially restored DA modulation of gamma oscillations in HRM. Third, inhibition of phosphatidylinositol 3-kinase (PI3K), a downstream molecule of NMDAR, increased gamma power and blocked the effects of DA on gamma oscillation in WTM and had no significant effect on gamma power but largely restored DA modulation of gamma oscillations in HRM. Our results reveal that impaired DA function in HRM is associated with dysregulated NMDAR-PI3K signaling, a mechanism that may be relevant in the pathology of schizophrenia.