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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 Article has an altmetric score of 18

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

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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 5

Restoration of social discrimination in Magel2+/–p mice by AVP injection in the dorsal LS.

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Restoration of social discrimination in Magel2+/–p mice by AVP injection...
(A) Experimental setup. (B) Change in EEG power spectrum with intraseptal injection of AVP (30 μM for 9 minutes starting 5 minutes before the first social trial) in Magel2+/+ mice. Data (mean ± SEM) of n = 13 NaCl and 10 AVP. Two-way ANOVA for AVP for 10 minutes: F 1,650 = 8.13, P = 0.004 and for 60 minutes: F1,650 = 15.5, P < 0.0001; post hoc Sidak test for pairwise comparisons between NaCl and AVP groups as indicated. (C) Time exploring a mouse upon injection of AVP (30 μM for 9 minutes starting 5 minutes before the first social trial) in dorsal LS of Magel2+/–p mice. Data (mean ± SEM) in n = 14 NaCl, 16 AVP-injected mice. Two-way ANOVA for social trials F2,42 = 17.99, P < 0.0001; AVP F1,21 = 0.03, P = 0.8; post hoc Sidak test comparing consecutive trials as indicated. (D) Change in EEG power spectrum with intraseptal injection of AVP during behavior. Data (mean ± SEM) of n = 14 NaCl and 9 AVP Magel2+/–p mice. Two-way ANOVA for AVP at novelty F23,504 = 1.27, P = 0.17 and at discrimination F23,480 = 1.74, P = 0.018; post hoc Sidak test for pairwise comparisons between NaCl and AVP groups as indicated. (E) Time exploring a mouse upon injection of Manning compound (MC, 10 nM for 9 minutes starting 5 minutes before the first social trial) in dorsal LS of Magel2+/+ mice. Data (mean ± SEM) in n = 15 NaCl, 11 MC Magel2+/+ mice. Two-way ANOVA: social trials F2,48 = 11.12, P = 0.0001; MC F1,24 = 2.46, P = 0.12; post hoc Dunnett test for pairwise comparison between consecutive trials as indicated. (F) Change in EEG power spectrum with intraseptal injection of MC during behavior. Data (mean ± SEM) expressed as percentage relative to baseline in n = 17 NaCl, 11 MC. Two-way ANOVA for social novelty F25,650 = 2.83, P < 0.0001; MC F1,650 = 2.56, P = 0.1; social discrimination F25,676 = 0.6, P = 0.9; MC F1,676 = 31.3, P < 0.0001; post hoc Sidak test for pairwise comparison between NaCl and MC groups as indicated.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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