Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia

Given its high penetrance, clearly delineated and evolutionary conserved genomic structure, mouse models of the 22q11.2 deletion provide an ideal organism-based and cell-based model of this well-established disease mutation for schizophrenia. In this study we examined the development of changes in intrinsic properties, action potential firing and synaptic transmission using whole-cell patch-clamp recordings of cultured embryonic cortical neurons from Df(16)A(+/−) and WT mice at DIV7 and DIV14, respectively. Compared to neurons from the WT littermates, significantly increased input resistance and decreased rising rate of action potential was observed in Df(16)A(+/−) mice at DIV7 but not at DIV14 indicative of delayed neuronal maturation. Neurons from Df(16)A(+/−) mice also showed significantly higher cellular excitability at both DIV7 and DIV14. Evaluation of Ca(2+) homeostasis perturbation caused by 22q11.2 deletion using calcium imaging revealed a significantly lower amplitude of calcium elevation and a smaller area under the curve after depolarization in neurons from Df(16)A(+/−) mice at both DIV7 and DIV14. Furthermore, the properties of inhibitory synaptic events were significantly altered in Df(16)A(+/−) mice. We identified changes in mRNA expression profiles, especially in ion channels, receptors, and transporters that may underlie the neurophysiological effects of this mutation. Overall, we show a number of alterations in electrophysiological and calcium homeostatic properties of embryonic cortical neurons from a 22q11.2 deletion mouse model at different culture times and provide valuable insights towards revealing disease mechanisms and discovery of new therapeutic compounds.