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.
View: Text | PDF
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

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

×

Figure 3

Magel2 deficiency decreases AVP receptor levels in SST neurons of the dorsal LS.

Options: View larger image (or click on image) Download as PowerPoint
Magel2 deficiency decreases AVP receptor levels in SST neurons of the d...
(A) Regional precision of 1 nM [125I]LVA binding without (total) and with (nonspecific) unlabeled AVP in excess on frozen brain sections of Magel2+/+ and Magel2+/–p mice. Data (mean ± SEM) expressed as a percentage relative to Magel2+/+ in n = 8 Magel2+/+ and 7 Magel2+/–p mice. Two-way ANOVA: genotype F1,26 = 2.08, P = 0.16; effect of subregions in LS F1,26 = 0.13, P = 0.71; post hoc Sidak test for comparisons. (B) Cellular precision of 50 μM d[Lys(Alexa Fluor 647)8]VP binding without (total, n = 4 mice) and with (nonspecific, n = 3 mice) 100 μM Manning compound injected directly into the LS of Magel2+/+ mice. OXTR competitor (5 μM TGOT, n = 5 mice) coinjected with d[Lys(Alexa Fluor 647)8]VP to specify AVPR binding sites representative of 3 independent experiments. Scale bar: 1 mm. Binding affinity for AVPR subtypes presented in Supplemental Table 1. (C) Coexpression of AVPR binding sites with the indicated markers. Arrows point to cells with “bright” labeling and arrowheads to cells with “dim” labeling. Scale bars: 25 μm. Percentage of cells coexpressing AVPR and cell markers are indicated. (D) Proportion of cell types with AVPR binding sites for d[Lys(Alexa Fluor 647)8]VP in dorsal LS. Data (mean ± SEM) expressed as percentage relative to Magel2+/+ in n = 6 Magel2+/+ and 6 Magel2+/–p mice. Three-way ANOVA for cell type F2,59 = 37.27, P < 0.0001; AVPR binding F1,59 = 49.85, P < 0.0001; genotype F1,59 = 1.83, P = 0.18; cell type × AVPR binding × genotype F2,59 = 5.35, P = 0.0073; post hoc Sidak test results as indicated.