TMEM16B Calcium-Activated Chloride Channels Regulate Action Potential Firing in Lateral Septum and Aggression in Male Mice

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.

Calcium- and Voltage-Dependent Dual Gating ANO1 is an Intrinsic Determinant of Repolarization in Rod Bipolar Cells of the Mouse Retina

“…These results suggest that ANO1 contributes to the rapid repolarization process. It is consistent with previous studies about modulation of the action potential by ANO1 or ANO2, which showed elongation of the excitation by Cl − inhibition [29,55].…”

TMEM16B regulates anxiety-related behavior and GABAergic neuronal signaling in the central lateral amygdala

“…Given that TMEM16B-CaCC is expressed in the hippocampus, lateral septum, and Inferior olive neurons, where it is activated by Ca 2+ influx through voltage-gated Ca 2+ channels (Huang et al, 2012; Wang et al, 2019; Zhang et al, 2017), we tested whether TMEM16B can also be activated by Ca 2+ influx through voltage-gated Ca 2+ channels in neurons of central lateral amygdala. First, we confirmed that Ca 2+ currents were elicited in SOM + neurons with depolarizations lasting 60 ms (Figure 4—figure supplement 1A).…”

“…TMEM16B expression is mainly confined to the nervous system, including the olfactory neurons (Billig et al, 2011; Pietra et al, 2016), retina (Mercer et al, 2011; Stöhr et al, 2009), hippocampus (Huang et al, 2012), lateral septum (Wang et al, 2019), and inferior olive neurons (Zhang et al, 2017). In the hippocampus, lateral septum and inferior olive, TMEM16B modulates action potentials and neuronal excitability.…”

“…TMEM16B is known to serve important functions in various brain regions including the hippocampus (Ha et al, 2016; Huang et al, 2012; Neureither et al, 2017; Wang et al, 2019; Zhang et al, 2015; Zhang et al, 2017), however, whether it also modulates neuronal signaling in the amygdala remains an open question. We found that TMEM16B-CaCC is highly enriched in central lateral amygdala (CeL).…”

A Human Accelerated Region is a Leydig cellGLI2Enhancer that Affects Male-Typical Behavior

“…The intruder dominance score is the total bouts of following, sniffing, mounting, licking, circling, tail grabs, and pushing during each 10-minute Resident Intruder session. Detail of procedure in ( 57, 60, 61 ).…”