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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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 4

Magel2 deficiency reduces neuronal response to AVP in the dorsal LS.

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Magel2 deficiency reduces neuronal response to AVP in the dorsal LS. (A...
(A) Typical firing patterns of dorsal LS neurons in coronal slices at baseline and upon 2-minute bath application of 1 μM AVP (whole cell recordings). Responses representative of more than 5 experiments reverted to baseline after washout. (B) Frequency of action potentials in AVP-excited cells. Mean ± SEM expressed as percentage relative to baseline prior to AVP stimulation (gray bar). Numbers indicate cells excited (blue) and insensitive to AVP (black). Three-way ANOVA for time F30,2259 = 9.5, P < 0.0001; AVP F1,76 = 16.9, P < 0.0001; genotype F1,76 = 1.2, P > 0.2; time × AVP F30,2259 = 8.6, P < 0.0001; time × AVP × genotype F30,2259 = 1.04, P = 0.4; post hoc Tukey test. (C) Frequency of action potentials in AVP-inhibited cells. Mean ± SEM expressed as percentage relative to baseline. Numbers indicate cells excited (blue) and insensitive to AVP (black, same as in panel B). Three-way ANOVA for time F30,2077 = 2.55, P < 0.0001; AVP F1,71 = 4.9, P = 0.03; genotype F1,71 = 0.6, P > 0.4; time × AVP F30,2077 = 3.05, P < 0.0001; time × AVP × genotype F30,2077 = 0.4, P > 0.9; post hoc Tukey test. (D) Proportion of cells categorized according to their responses to AVP on the frequency of action potentials recorded in loose patch (n = 32 Magel2+/+, 26 Magel2+/–p cells) or whole cell (n = 103 Magel2+/+, 45 Magel2+/–p cells) configurations. Comparisons between Magel2+/+ and Magel2+/–p: χ2(2) = 11.47, **P = 0.003 and χ2(2) = 13.22, **P = 0.0013. (E) AVP-inhibited cell representative of at least 2 independent experiments marked with cadaverine dye injected in the patch pipette and labeled with SST antibodies. (F) Effect of AVP on the frequency of synaptic events in dorsal LS neurons from Magel2+/+ mice representative of more than 5 experiments. Effect sizes are presented in Table 1.