TMEM16B Calcium-Activated Chloride Channels Regulate Action Potential Firing in Lateral Septum and Aggression in Male Mice
- Lynn Wang1,2,4,
- Jeffrey Simms3,
- Christian J. Peters2,4,5,
- Marena Tynan-La Fontaine2,4,
- Kexin Li2,4,
- T. Michael Gill3,
- Yuh Nung Jan2,4, and
- Lily Y. Jan2,4
- 1Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94143,
- 2Department of Physiology, University of California San Francisco, San Francisco, California 94143,
- 3Gladstone Institutes Behavioral Core, San Francisco, California 94158,
- 4Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, and
- 5Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612
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Author contributions: L.W., J.S., C.J.P., T.M.G., Y.N.J., and L.Y.J. designed research; L.W., J.S., and M.T.-L.F. performed research; L.W. and J.S. analyzed data; L.W. wrote the first draft of the paper; L.W., J.S., C.J.P., K.L., T.M.G., Y.N.J., and L.Y.J. edited the paper; L.W., C.J.P., and L.Y.J. wrote the paper; K.L. contributed unpublished reagents/analytic tools.
Abstract
The lateral septum (LS) plays an important role in regulating aggression. It is well recognized that LS lesions lead to a dramatic increase in aggressive behaviors. A better understanding of LS neurophysiology and its functional output is therefore important to assess LS involvement in regulating aggression. The LS is a heterogeneous structure that maintains inputs and outputs with multiple brain regions, and is also divided into subregions that innervate one another. Thus, it is challenging to identify the exact cell type and projections for characterization. In this study, we determined the expression pattern of the calcium-activated chloride channel, TMEM16B, in the LS of both male and female mice. We then investigated the physiological contribution of the calcium-activated chloride channel to LS neuronal signaling. By performing whole-cell patch-clamp recording, we showed that TMEM16B alters neurotransmitter release at the hippocampal-LS synapse, and regulates spike frequency and spike frequency adaptation in subpopulations of LS neurons. We further demonstrated that loss of TMEM16B function promotes lengthened displays of aggressive behaviors by male mice during the resident intruder paradigm. In conclusion, our findings suggest that TMEM16B function contributes to neuronal excitability in subpopulations of LS neurons and the regulation of aggression in male mice.
SIGNIFICANCE STATEMENT Aggression is a behavior that arose evolutionarily from the necessity to compete for limited resources and survival. One particular brain region involved in aggression is the lateral septum (LS). In this study, we characterized the expression of the TMEM16B calcium-activated chloride channel in the LS and showed that TMEM16B regulates the action potential firing frequency of LS neurons. We discovered that loss of TMEM16B function lengthens the displays of aggressive behaviors in male mice. These findings suggest that TMEM16B plays an important role in regulating LS neuronal excitability and behaviors associated with LS function, thereby contributing to our understanding of how the LS may regulate aggression.
- Received December 14, 2018.
- Revision received June 11, 2019.
- Accepted July 11, 2019.
- Copyright © 2019 the authors
