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 2

Magel2 deficiency increases c-Fos expression in SST neurons of the dorsal LS during social exploration.

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Magel2 deficiency increases c-Fos expression in SST neurons of the dors...
(A) c-Fos induction representative of n = 5 Magel2+/+ mouse interacting with a new conspecific for 5 minutes, euthanized 15 minutes later (left) compared with 5 Magel2+/+ mice interacting with a new object in the same conditions (right). (B) c-Fos induction in the septum representative of the mice making 0 to 5 social trials analyzed in panel C. All mice were euthanized 15 minutes after the last trial. (C) Number of c-Fos+ cells/mm2 in a total of 28,072 Magel2+/+ and 38,534 Magel2+/–p cells. Mean ± SEM of n = 5 controls, 5 novelty, 4 habituation, 4 discrimination Magel2+/+ and 7, 5, 4, 9 Magel2+/–p mice, respectively. Two-way ANOVA for social trials in Magel2+/+ F3,56 = 31.7, P < 0.0001; in Magel2+/–p F3,88 = 6.871, P = 0.0003; septal regions in Magel2+/+ F3,56 = 2.95, P = 0.04; and in Magel2+/–p F3,56 = 2.39, P = 0.07; post hoc Dunnett test results as indicated. Multiple comparison between genotypes by Wilcoxon unpaired t test at novelty in medial septum (MS) t(8) = 3.5, P = 0.007 and LSV t(8) = 2.8, P = 0.02; at habituation in MS t(6) = 2.76, P = 0.032. (D) Percentage of SST cells with c-Fos expression in the LSD of Magel2+/+ and Magel2+/–p mice (stars mark double-positive cells). Mean ± SEM of n = 7 controls, 6 novelty, 7 habituation, 7 discrimination, 5 novelty + 2 hours for Magel2+/+ and 7, 5, 6, 6, 5 for Magel2+/–p mice, respectively. Two-way ANOVA for genotype F1,52 = 14.05, P = 0.0004; trials F4,52 = 18.36, P < 0.0001; post hoc Sidak test results as indicated. Arrows mark euthanization 15 minutes after the last trial. (E) Percentage of SST cells with c-Fos expression in the LSD of Magel2+/+ mice (stars mark double-positive cells). Mean ± SEM of n = 5 NaCl, 5 AVP, 4 TGOT mice injected in dorsal LS via bilateral cannula and euthanized 15 minutes later. Kruskal-Wallis test, P = 0.0012, post hoc Dunn test results as indicated. LSD, lateral septum dorsal; LSV, lateral septum ventral.