Development And Molecular Mechanisms Of GABA Circuitry In The Mouse Prefrontal Cortex

The prefrontal cortex (PFC) is responsible for higher cognitive functions such as working memory, during which parvalbumin-positive fast-spiking (FS) interneurons play an essential role. FS interneurons account for40-50%of all interneurons in the neocortex, a large majority of which are basket cells; these neurons form several microcircuits in the PFC:first, they are connected with pyramidal neurons (PN) through chemical synapses (FS-PN); second, they are interconnected via chemical and electrical synapses (FS-FS). In addition, FS interneurons also receive synaptic inputs from thalamo-cortical relay neurons, and project to and receive inputs from somatostatin-expressing interneurons. Despite the putative relevance of FS interneurons for neurodevelopmental disease processes such as schizophrenia in humans, to the best of our knowledge, little effort has been exerted to study when and how FS interneurons develop their networks in the PFC.The development of GABA circuitry is regulated by many factors. Among them are neurotrophins like BDNF and FGF. Neuregulin1(NRG1), a member of the growth factor family, functions in a number of developmental processes mainly through binding with the tyrosine kinase-type receptor ErbB4in the central nervous system. Both nrgl and erbb4are susceptibility genes for schizophrenia, yet their precise roles in schizophrenia are largely unknown. Recent studies show that ErbB4is expressed predominantly in interneurons, specifically, in FS interneurons. However, it is largely unknown what roles NRG1-ErbB4signals play during the development of FS interneuronal microcircuits, particularly that mediated by basket cells in the PFC.Here, with the use of a combination of research disciplines including molecular genetics, biochemistry, and electrophysiology, we demonstrate that in the mouse PFC, FS interneurons were poorly developed in terms of the membrane and network properties during the first postnatal week, both of which exhibited an abrupt maturation during the second postnatal week. The development of FS interneuronal microcircuits persisted throughout early adulthood. NRG1-ErbB4signaling was dispensable for the development of GABAergic synapses and gap junctions formed by FS basket interneurons in vivo. However, activity-dependent GABAergic FS-PN transmissions were disrupted without erbb4. While NRG1-ErbB4signaling was not required for the early development of glutamatergic synapses on FS basket interneurons, it was essential for the maturation of these synapses. Based on these observations, we speculate the following model:NRG1-ErbB4signaling is required for the development of glutamatergic synapses, but not GABAergic synapses. Knock-out of ErbB4leads to hypo-glutamatergic transmissions on FS basket interneurons and reduced activity-dependent GABAergic FS-PN transmissions, thus reducing inhibition mediated by FS basket interneurons. To maintain the appropriate excitation/inhibition (E/I) balance, PN neurons then homeostatically reduce the glutamatergic excitatory synapses. The disruption of E/I balance during adolescence may underlie the etiology of neuropsychiatric disorders like schizophrenia.