Edited by Hee-Sup Shin, Institute for Basic Science, Daejeon, Republic of Korea, and approved September 11, 2018 (received for review July 16, 2018)
Our ability to reason, feel, and socialize relies on the development of a tight balance between inhibition and excitation within cortical circuits. The growth factor BDNF and its receptor TrkB are important for inhibitory neuron development and have been implicated in neuropsychiatric disorders. However, the behavioral consequences of impaired BDNF/TrkB signaling are unknown. Using a transgenic mouse line, we show that mice with deletion of BDNF/TrkB signaling from cortical inhibitory neurons exhibit social dominance and decreased inhibition within the prefrontal cortex, a key region regulating social behavior. Reversal of the network imbalance with optogenetic inhibition could rescue the behavior. Our results reveal a previously uncharacterized role of growth factor signaling within cortical interneurons for the development of social cognition.
The tight balance between synaptic 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, largely due to confounding motor function deficits observed in previous animal models. 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 showed intact motor coordination and movement, but exhibited 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 medial prefrontal cortex (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 role of BDNF/TrkB signaling in inhibitory synaptic modulation and social dominance behavior in mice.
Author contributions: S.T. and H.S.J. designed research; S.T. and Y.X. performed research; H.H.Y., A.I.C., and T.W.S. contributed new reagents/analytic tools; S.T., Y.X., and H.S.J. analyzed data; and S.T. and H.S.J. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
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