LOSS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) SIGNALLING IN CORTICO-LIMBIC INTERNEURONS IMPAIRS ELECTROPHYSIOLOGICAL MATURATION AND LEADS TO ANXIETY AND SOCIAL DOMINANCE IN MICE

Abstract

The tight balance between excitation and inhibition (E/I) within neocortical circuits in the mammalian brain is important for complex behavior. Many loss-of-function studies have demonstrated that brain-derived neurotrophic factor (BDNF) and its cognate receptor tropomyosin receptor kinase B (TrkB) are essential for the development of inhibitory GABAergic neurons. However, behavioral consequences of impaired BDNF/TrkB signaling in GABAergic neurons remain unclear. In this study, we generated conditional knockout mice (TrkB cKO) in which TrkB was ablated from a majority of corticolimbic GABAergic interneurons postnatally. These mice exhibited anxiety and enhanced dominance over other mice in a group-housed setting. In addition, immature fast-spiking GABAergic neurons of TrkB cKO mice resulted in an E/I imbalance in layer 5 microcircuits within the mPFC, a key region regulating social dominance. Restoring the E/I imbalance via optogenetic modulation in the mPFC of TrkB cKO mice normalized their social dominance behavior. Taken together, our results provide strong evidence for a novel role of BDNF/TrkB signaling in inhibitory synaptic modulation, anxiety and social dominance in mice.