Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model
Amélie M. Borie, … , Michel G. Desarménien, Freddy Jeanneteau
Amélie M. Borie, … , Michel G. Desarménien, Freddy Jeanneteau
Published November 24, 2020
Citation Information: J Clin Invest. 2021;131(2):e144450. https://doi.org/10.1172/JCI144450.
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Research Article Neuroscience

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model

Abstract

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.

Authors

Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarménien, Freddy Jeanneteau

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Figure 7

Correction of social disabilities in Magel2-deficient mice with optogenetic stimulation of AVP neurons in the BNST/LS pathway correlates with the deactivation of SST neurons in the dorsal LS.

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Correction of social disabilities in Magel2-deficient mice with optogene...
(A) Viral strategy to express ChR2 in AVP neurons of 2 distinct regions with established projections in the LS where optic fibers were implanted to manipulate AVP responses during social behavior. (B) Expression of Cre-dependent ChR2-YFP in AVP neurons in the BNST or in the PVN of Magel2+/–p mice. Percentage (mean ± SEM) of AVP neurons expressing ChR2-YFP in BNST or PVN of 6 Magel2+/–p mice per group. (C) Time exploring a mouse upon stimulation of ChR2 with blue light (473 nm, 20 Hz, 5 ms pulses for 9 minutes during social novelty) in dorsal LS projections from AVP neurons of the BNST or the PVN in Magel2+/–p mice. Mean ± SEM of n = 6 no light, 6 blue light for the BNST/LS groups and 9 no light, 11 blue light for the PVN/LS groups. Two-way ANOVA for the BNST/LS pathway: effect of social trials F2,10 = 17.11, P = 0.0006 and interaction with CHR2 stimulation F2,10 = 3.6, P = 0.06; for the PVN/LS pathway: effect of social trials F2,36 = 9.17, P = 0.0006 and interaction with ChR2 stimulation F2,36 = 4.19, P = 0.02; post hoc Sidak test for pairwise comparisons. (D) Change in EEG power spectrum with intraseptal stimulation of ChR2 during social novelty. Mean ± SEM expressed as percentage relative to baseline in n = 11 no light, 6 blue light. Two-way ANOVA for the effect of blue light on frequency at T1 F1,390 = 18.27, P < 0.0001 and at T5 F25,400 = 1.73, P = 0.016. (E) Percentage of SST neurons expressing c-Fos in dorsal LS 15 minutes after the social discrimination trial (time of euthanization). Stars mark colabeled cells. Mean ± SEM of 6 Magel2+/–p mice per group. Kruskal-Wallis test, P = 0.011; post hoc Dunn test results as indicated.