Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model
Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarménien, Freddy Jeanneteau
Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarménien, Freddy Jeanneteau
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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 6

Magel2 deficiency impairs the number of fibers projecting in the dorsal LS and activation of the PVN AVP neurons by social stimuli.

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Magel2 deficiency impairs the number of fibers projecting in the dorsal...
(A) Neurophysin II (AVP) immunoreactivity and semiautomated fiber tracing in the septum representative of the number of mice analyzed in panel B. (B) Number of AVP fibers in 5 Magel2+/+, 5 Magel2+/–p mice sorted as a function of length. Kolmogorov-Smirnov test, P < 0.0001. (C) Induction of c-Fos in AVP neurons of the paraventricular hypothalamic nucleus (PVN), lateral hypothalamus (LH), supraoptic nucleus (SON), and bed nucleus of stria terminalis (BNST) after social novelty representative of the number of mice analyzed in panel D. Scale bars: 50 μm. (D) Percentage of AVP neurons expressing c-Fos after social tasks (euthanized 15 minutes after trial 5). Mean ± SEM of n = 8 controls, 8 novelty, 12 habituation, 7 discrimination Magel2+/+ and 9, 8, 5, 5 Magel2+/–p mice, respectively. Two-way ANOVA for social trials in Magel2+/+ F3,96 = 4.34, P = 0.006 and in Magel2+/–p F3,76 = 2.07, P = 0.11; regional AVP neurons in Magel2+/+ F3,96 = 23.76, P < 0.0001 and in Magel2+/–p F3,75 = 1.76, P = 0.16; social trials × regional AVP neurons in Magel2+/+ F9,96 = 4.36, P < 0.0001 and in Magel2+/–p F9,75 = 1.17, P = 0.32; post hoc Dunnett test results as indicated. Multiple comparison between Magel2+/+ and Magel2+/–p by Sidak test in the PVN t(8) = 3.05, P = 0.038 and in the BNST t(6) = 4.5, P = 0.0002 at novelty.