A Schizophrenia-Related Deletion Leads to KCNQ2-Dependent Abnormal Dopaminergic Modulation of Prefrontal Cortical Interneuron Activity

作者：Choi Se Joon; Mukai Jun; Kvajo Mirna; Xu Bin; Diamantopoulou Anastasia; Pitychoutis Pothitos M; Gou Bin; Gogos Joseph A^*; Zhang Hui^*

来源：Cerebral Cortex, 2018, 28(6): 2175-2191.

DOI：10.1093/cercor/bhx123

• dopamine
• interneuron
• KCNQ
• prefrontal cortex
• schizophrenia

Altered prefrontal cortex function is implicated in schizophrenia (SCZ) pathophysiology and could arise from imbalance between excitation and inhibition (E/I) in local circuits. It remains unclear whether and how such imbalances relate to genetic etiologies. We used a mouse model of the SCZ-predisposing 22q11.2 deletion (Df(16) A(+/-) mice) to evaluate how this genetic lesion affects the excitability of layer V prefrontal pyramidal neurons and its modulation by dopamine (DA). Df(16) A(+/-) mice have normal balance between E/I at baseline but are unable to maintain it upon dopaminergic challenge. Specifically, in wild-type mice, D1 receptor (D1R) activation enhances excitability of layer V prefrontal pyramidal neurons and D2 receptor (D2R) activation reduces it. Whereas the excitatory effect upon D1R activation is enhanced in Df(16) A(+/-) mice, the inhibitory effect upon D2R activation is reduced. The latter is partly due to the inability of mutant mice to activate GABAergic parvalbumin (PV)+ interneurons through D2Rs. We further demonstrate that reduced KCNQ2 channel function in PV+ interneurons in Df(16) A(+/-) mice renders them less capable of inhibiting pyramidal neurons upon D2 modulation. Thus, DA modulation of PV+ interneurons and control of E/I are altered in Df(16) A(+/-) mice with a higher excitation and lower inhibition during dopaminergic modulation.

• 出版日期2018-6