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 7

Inhibiting MSGABA-innervated CA2 or POA neurons selectively impairs social memory or reduces sleep, respectively, in C57BL/6J mice.

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Inhibiting MSGABA-innervated CA2 or POA neurons selectively impairs soci...
(A) Schematic of the experimental procedure. (B) Schematic for labeling MSGABA→CA2 neurons in C57BL/6J mice. (C) Raster plot (top) and peristimulus time histogram (bottom) of a CA2 neuron innervated by MSGABA neurons. (D and E) Quantification of sniffing time (D, n = 12 mice, F[2, 33] = 128.8) and social novelty index (E, F[1.84, 20.23] = 175.1) by inactivation of MSGABA-innervated CA2 neurons in C57BL/6J mice during the social novelty test. (F) Representative EEG spectrogram (top), relative EMG trace (middle), and brain states (bottom) from a C57BL/6J mouse. Yellow stripe indicates laser stimulation (589 nm, 8 seconds on/2 seconds off, 120 seconds). (G) No significant change in NREM sleep (P = 0.192), wakefulness (P = 0.349), and REM sleep (P = 0.376) during laser stimulation (n = 12 mice). Shading represents ±SEM. (H) Similar to B, but for labeling MSGABA→POA neurons. (I) Similar to C, but for an MSGABA-innervated POA neuron. (J and K) Quantification of sniffing time (J, n = 13 mice, F[2, 36] = 3.865, P = 0.03) and social novelty index (K, F[1.52, 18.25] = 0.643, P = 0.496) by inactivation of MSGABA-innervated POA neurons in C57BL/6J mice during the social novelty test. (L) Similar to F, but for inactivation of MSGABA-innervated POA neurons. (M) Optogenetic inactivation of MSGABA-innervated POA neurons (589 nm, yellow laser, 8 seconds on/2 seconds off, 120 seconds) significantly decreased in NREM sleep (n = 13 mice), increased in wakefulness, and did not affect REM sleep (P = 0.336). Shading represents ±SEM. ***P < 0.001; ###P < 0.001 by 2-way (D and J) or 1-way (E and K) repeated-measures ANOVA with Bonferroni’s post hoc test, or bootstrap test (G and M). NS, not significant.