Development of GABA Circuitry of Fast-Spiking Basket Interneurons in the Medial Prefrontal Cortex oferbb4-Mutant Mice

Abstract

erbb4 is a susceptibility gene for schizophrenia and ErbB4 signals have been hypothesized to function in a number of cortical developmental processes (Silberberg et al., 2006; Mei and Xiong, 2008). Several recent studies show that the expression of ErbB4 is mainly restricted to GABAergic interneurons (Yau et al., 2003; Woo et al., 2007), specifically, to parvalbumin-positive (PV) fast-spiking (FS) interneurons (Vullhorst et al., 2009; Fazzari et al., 2010), a large majority of which are PV FS basket cells (Kawaguchi, 1995; Taniguchi et al., 2013). However, in the medial prefrontal cortex (mPFC), a brain region that is closely associated with neuropsychiatric disorders including schizophrenia, little is known about the roles of ErbB4 signals during the development of GABAergic circuitry particularly that associated with PV FS basket cells. Here, using molecular genetics, biochemistry, and electrophysiology, we deleted ErbB4 receptors in GABAergic forebrain neurons during the embryonic period and demonstrated that in the mouse mPFC, ErbB4 signals were dispensable for the development of GABAergic synapses by PV FS basket cells. Interestingly, they were required for the final maturation rather than the initial formation of glutamatergic synapses on PV FS basket cells. Furthermore, activity-dependent GABAergic PV FS pyramidal neuron transmission was decreased, whereas activity of pyramidal neurons was increased in KO mice. Together, these data indicate that ErbB4 signals contribute to the development of GABAergic circuitry associated with FS basket cells in component- and stage-dependent manners in the mPFC in vivo, and may suggest a mechanism for neuropsychiatric disorders including schizophrenia.