Autism-associated neuroligin 3 deficiency in medial septum causes social deficits and sleep loss in mice
Haiyan Sun, Yu Shen, Pengtao Ni, Xin Liu, Yan Li, Zhentong Qiu, Jiawen Su, Yihan Wang, Miao Wu, Xiangxi Kong, Jun-Li Cao, Wei Xie, Shuming An
Haiyan Sun, Yu Shen, Pengtao Ni, Xin Liu, Yan Li, Zhentong Qiu, Jiawen Su, Yihan Wang, Miao Wu, Xiangxi Kong, Jun-Li Cao, Wei Xie, Shuming An
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Research Article Neuroscience

Autism-associated neuroligin 3 deficiency in medial septum causes social deficits and sleep loss in mice

Abstract

Patients with autism spectrum disorder (ASD) frequently experience sleep disturbance. Genetic mutations in the neuroligin 3 (NLG3) gene are highly correlative with ASD and sleep disturbance. However, the cellular and neural circuit bases of this correlation remain elusive. Here, we found that the conditional knockout of Nlg3 (Nlg3-CKO) in the medial septum (MS) impairs social memory and reduces sleep. Nlg3 CKO in the MS caused hyperactivity of MSGABA neurons during social avoidance and wakefulness. Activation of MSGABA neurons induced social memory deficits and sleep loss in C57BL/6J mice. In contrast, inactivation of these neurons ameliorated social memory deficits and sleep loss in Nlg3-CKO mice. Sleep deprivation led to social memory deficits, while social isolation caused sleep loss, both resulting in a reduction in NLG3 expression and an increase in activity of GABAergic neurons in the MS from C57BL/6J mice. Furthermore, MSGABA-innervated CA2 neurons specifically regulated social memory without impacting sleep, whereas MSGABA-innervating neurons in the preoptic area selectively controlled sleep without affecting social behavior. Together, these findings demonstrate that the hyperactive MSGABA neurons impair social memory and disrupt sleep resulting from Nlg3 CKO in the MS, and achieve the modality specificity through their divergent downstream targets.

Authors

Haiyan Sun, Yu Shen, Pengtao Ni, Xin Liu, Yan Li, Zhentong Qiu, Jiawen Su, Yihan Wang, Miao Wu, Xiangxi Kong, Jun-Li Cao, Wei Xie, Shuming An

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Figure 2

Nlg3 knockout in the MS causes hyperactivity of MSGABA neurons during social avoidance and wakefulness.

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Nlg3 knockout in the MS causes hyperactivity of MSGABA neurons during s...
(A–C) Representative FISH images (A and B) and quantification of c-Fos expression in MS between control and Nlg3-CKO mice (C, n = 5 mice). Scale bars: 200 μm (left) and 20 μm (right). (D) Quantification of the overlap between c-Fos+ cells and Vgat (n = 5 mice). (E and F) Schematic diagram for experimental protocols and optrode recording. (G) Representative images of the MS from an Nlg3-CKO mouse. Scale bars: 200 μm (left) and 20 μm (right). (H) Optogenetic tagging and identification of MSGABA neuron. Waveforms (top), a representative raw trace (middle), and raster plots (down) from an identified MSGABA neuron. (I–K) Example recording of spontaneous spikes (I) and mean firing rates (J, shading represents ±SEM) and quantification of the identified MSGABA neurons from control and Nlg3-CKO mice (K, n = 38 units from 7 mice, F[1, 74] = 157.9) during the approach and avoidance of a novel mouse. (L and M) Representative trace of firing rate from a MSGABA neuron (L) and quantification of the identified MSGABA neurons in control mice and Nlg3-CKO mice (M, n = 48 units from 9 mice, F[2, 188] = 59.83) during wakefulness, NREM, and REM sleep. (N) Firing rate modulation of identified MSGABA neuron from both control and Nlg3-CKO mice. W, wake; R, REM; NR, NREM. (O) Mean firing rates of identified MSGABA neurons from both mice during different brain state transitions. Shading represents ±SEM. **P < 0.01; ***P < 0.001; ###P < 0.001 by 2-tailed Mann-Whitney test (C and N) or 2-way ANOVA with Bonferroni’s post hoc test (K and M). NS, not significant.