Autism-associated neuroligin 3 deficiency in medial septum causes social deficits and sleep loss in mice
Haiyan Sun, … , Wei Xie, Shuming An
Haiyan Sun, … , Wei Xie, Shuming An
Published July 26, 2024
Citation Information: J Clin Invest. 2024;134(19):e176770. https://doi.org/10.1172/JCI176770.
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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 3

Activating MSGABA neurons induces social memory deficits and sleep loss in C57BL/6J mice.

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Activating MSGABA neurons induces social memory deficits and sleep loss ...
(A) Schematic diagram of the experimental procedure. (B) AAV2-GAD67-hChR2-eGFP was injected into the MS and blue laser light (473 nm, 10 Hz) was applied to the MS. (C) Representative image showing selective transduction of hChR2-eGFP in the MS where an optical fiber is located. Scale bar: 200 μm. (D) Representative images showing hChR2-eGFP–expressing neurons colocalized with Vgat. Scale bar: 20 μm. (E–G) Representative heatmaps (E) and quantification of sniffing time (F; n = 12 mice, F[2, 33] = 5.811) and sociability index (G, F[1.26, 13.9] = 2.692) in MSGAD67-ChR2 mice during the sociability test. (H–J) Representative heatmaps (H) and quantification of sniffing time (I; F[2, 33] = 116.8) and social novelty index (J, F[1.74, 19.13] = 132.3) in MSGAD67-ChR2 mice during the social novelty test. (K) Representative EEG spectrogram (top), EMG trace (middle), and brain states (bottom) from a MSGAD67-ChR2 mouse. Blue stripe indicates laser stimulation (473 nm, 10 Hz, 120 seconds). (L) Percentage of time in different brain states before, during, and after blue laser (473 nm, 10 Hz, 120 seconds) activation of MSGABA neurons (n = 12 mice, NREM, REM, and Wake). Shading represents ±SEM. (M) The changes in transition probability between each pair of brain states in MSGAD67-ChR2 mice during blue laser stimulation. (N and O) No significant change in percentage of time in different brain states (N, n = 10 mice, NREM, P = 0.189; wake, P = 0.196; REM, P = 0.13) and transition probability (O, P > 0.05) in MSGAD67-eGFP control mice. *P < 0.05; ***P < 0.001; #P < 0.05; ##P < 0.01; ###P < 0.001 by 2-way (F and I) or 1-way (G and J) repeated-measures ANOVA with Bonferroni’s post hoc test, or bootstrap test (L–O). NS, not significant.