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 8

Activating MSGABA-innervated CA2 or POA neurons selectively ameliorates social memory deficits or recovers lost sleep, respectively, in Nlg3-CKO mice.

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Activating MSGABA-innervated CA2 or POA neurons selectively ameliorates ...
(A) Schematic of the experimental procedure. (B) Schematic for labeling MSGABA→CA2 neurons in Nlg3-CKO mice. (C) Raster plot and peristimulus time histogram of a CA2 neuron innervated by MSGABA neurons. (D and E) Quantification of sniffing time (D, n = 8 mice, F[2, 21] = 141.3) and social novelty index (E, F[1.45, 10.14] = 99.7) by activation of MSGABA-innervated CA2 neurons in Nlg3-CKO mice during the social novelty test. (F) Representative EEG spectrogram, relative EMG trace, and brain states from an Nlg3-CKO mouse. Blue stripe indicates laser stimulation (473 nm, 10 Hz, 120 seconds). (G) No significant change in NREM sleep (n = 8 mice, P = 0.446), wakefulness (P = 0.125), and REM sleep (P = 0.465) during laser stimulation. Shading represents ±SEM. (H) Similar to A, but with a repetitive photostimulation paradigm to activate POA neurons for 1 hour before social tests. (I) Similar to B, but with fiber implantation into the POA. (J) Similar to C, but for an MSGABA-innervated POA neuron. (K and L) Activation of MSGABA-innervated POA neurons (473 nm, 10 Hz, 120 seconds) significantly increased in NREM sleep (n = 9 mice), decreased in both wakefulness and REM sleep. Shading represents ±SEM. (M and N) Quantification of sniffing time (M, n = 9 mice, F[2, 24] = 0.127, P = 0.881) and social novelty index (N, F[1.95, 15.57] = 0.81, P = 0.46) by activation of MSGABA-innervated POA neurons in Nlg3-CKO mice during the social novelty test. ***P < 0.001; ###P < 0.001 by 2-way (D and M) or 1-way (E and N) repeated-measures ANOVA with Bonferroni’s post hoc test, or bootstrap test (G and L). NS, not significant.