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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., Introduction Autism spectrum disorders (ASDs) affect 1 in 68 people and are characterized by difficulties with communication, restrictive interests, and repetitive behaviors influencing the ability to function properly (1). Treatment [...]

Although vasopressin V1B receptor (V1BR) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V1B agonist d[Leu4, Lys8]VP, either fluorescent or radioactive, we showed that V1BR is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V1BR were very low compared with the V2 receptor (V2R). On the microdissected IMCD, d[Leu4, Lys8]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca2 + concentration increase mobilization with an EC50 value in the nanomolar range. This effect involved both intracellular Ca2 + mobilization and extracellular Ca2 + influx. The selective V1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca2+ concentration but also cAMP, suggesting a cooperation between V1BR and V2R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V1B agonist triggered significant diuretic effects, in contrast with injection of selective V2 agonist. This study brings new data on the localization and signaling pathways of V1BR in the kidney, highlights a cross talk between V1BR and V2R in the IMCD, and suggests that V1BR may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V2R activation. [ABSTRACT FROM AUTHOR]

Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V1A and V1B receptors (R) are expressed in the liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glucose homeostasis in normal Sprague-Dawley rats, as well as the respective roles of V1AR and V1BR. We showed that acute injection of AVP induces a dose-dependent increase in glycemia. Pretreatment with a selective V1AR antagonist, but not a V1BR antagonist, dose-dependently prevented the rise in glycemia. V1BR antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective V1AR or V1BR agonists confirmed the involvement of V1AR in the hyperglycemic effect of AVP. In chronic experiments, AVP levels were altered in both directions. Sustained AVP infusion through implantable minipumps induced a time-dependent increase in fasting glycemia, whereas lowering endogenous AVP by increasing water intake had no effect. After 4 wk of AVP infusion, the rise in glycemia amounted to 1.1 mmol/l (P < 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a V1AR antagonist. Similar results were observed in lean Zucker rats. These findings demonstrate for the first time a causal link between chronic high AVP and hyperglycemia through V1AR activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes. [ABSTRACT FROM AUTHOR]

Confronting oxytocin and vasopressin deficits in autism spectrum disorders and rare syndromes brought promises and disappointments for the treatment of social disabilities. We searched downstream of oxytocin and vasopressin for targets alleviating social deficits in a mouse model of Prader-Willi syndrome and Schaaf-Yang syndrome, both associated with high prevalence of autism. We found a population of neurons in the lateral septum-activated on termination of social contacts-which oxytocin and vasopressin inhibit as per degree of peer affiliation. These are somatostatin neurons expressing oxytocin receptors coupled to GABA-B signaling, which are inhibited via GABA-A channels by vasopressin-excited GABA neurons. Loss of oxytocin or vasopressin signaling recapitulated the disease phenotype. By contrast, deactivation of somatostatin neurons or receptor signaling alleviated social deficits of disease models by increasing the duration of contacts with mates and strangers. These findings provide new insights into the treatment framework of social disabilities in neuropsychiatric disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although vasopressin V 1B receptor (V 1B R) mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using the selective V 1B agonist d[Leu 4 , Lys 8 ]VP, either fluorescent or radioactive, we showed that V 1B R is mainly present in principal cells of the inner medullary collecting duct (IMCD) in the male rat kidney. Protein and mRNA expression of V 1B R were very low compared with the V 2 receptor (V 2 R). On the microdissected IMCD, d[Leu 4 , Lys 8 ]VP had no effect on cAMP production but induced a dose-dependent and saturable intracellular Ca 2+ concentration increase mobilization with an EC 50 value in the nanomolar range. This effect involved both intracellular Ca 2+ mobilization and extracellular Ca 2+ influx. The selective V 1B antagonist SSR149415 strongly reduced the ability of vasopressin to increase intracellular Ca 2+ concentration but also cAMP, suggesting a cooperation between V 1B R and V 2 R in IMCD cells expressing both receptors. This cooperation arises from a cross talk between second messenger cascade involving PKC rather than receptor heterodimerization, as supported by potentiation of arginine vasopressin-stimulated cAMP production in human embryonic kidney-293 cells coexpressing the two receptor isoforms and negative results obtained by bioluminescence resonance energy transfer experiments. In vivo, only acute administration of high doses of V 1B agonist triggered significant diuretic effects, in contrast with injection of selective V 2 agonist. This study brings new data on the localization and signaling pathways of V 1B R in the kidney, highlights a cross talk between V 1B R and V 2 R in the IMCD, and suggests that V 1B R may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V 2 R activation. NEW & NOTEWORTHY Although V 1B R mRNA has been detected in the kidney, the precise renal localization as well as pharmacological and physiological properties of this receptor remain unknown. Using original pharmaceutical tools, this study brings new data on the localization and signaling pathways of V 1B R, highlights a cross talk between V 1B R and V 2 receptor (V 2 R) in the inner medullary collecting duct, and suggests that V 1B R may counterbalance in some pathophysiological conditions the antidiuretic effect triggered by V 2 R activation.

It is now accepted that vasopressin, through V 1A /V 1B receptors, centrally regulates cognitive functions such as memory, affiliation, stress, fear and depression. However, the respective roles of these receptor isoforms and their contribution to stress-related pathologies remain uncertain. The development of new therapeutic treatments requires a precise knowledge of the distribution of these receptors within the brain, which has been so far hampered by the lack of selective V 1B markers. In the present study, we have determined the pharmacological properties of three new potent rat V 1B fluorescent ligands and demonstrated that they constitute valuable tools for simultaneous visualization and activation of native V 1B receptors in living rat brain tissue. Thus, d[Leu 4 ,Lys-Alexa 647) 8 ]VP (analogue 3), the compound with the best affinity-selectivity/fluorescence ratio for the V 1B receptor emerged as the most promising. The rat brain regions most concerned by stress such as hippocampus, olfactory bulbs, cortex and amygdala display the highest V 1B fluorescent labelling with analogue 3. In the hippocampus CA 2 , V 1B receptors are located on glutamatergic, not GABAergic neurones, and are absent from astrocytes. Using AVP-EGFP rats, we demonstrate the presence of V 1B autoreceptors on AVP-secreting neurones not only in the hypothalamus, but also sparsely in the hippocampus. Finally, using both electrophysiology and visualization of ERK phosphorylation, we show analogue 3-induced activation of the V 1B receptor in situ. This will help to analyse expression and functionality of V 1B receptors in the brain and contribute to further explore the AVPergic circuitry in normal and pathological conditions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V 1A and V 1B receptors (R) are expressed in the liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glucose homeostasis in normal Sprague-Dawley rats, as well as the respective roles of V 1A R and V 1B R. We showed that acute injection of AVP induces a dose-dependent increase in glycemia. Pretreatment with a selective V 1A R antagonist, but not a V 1B R antagonist, dose-dependently prevented the rise in glycemia. V 1B R antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective V 1A R or V 1B R agonists confirmed the involvement of V 1A R in the hyperglycemic effect of AVP. In chronic experiments, AVP levels were altered in both directions. Sustained AVP infusion through implantable minipumps induced a time-dependent increase in fasting glycemia, whereas lowering endogenous AVP by increasing water intake had no effect. After 4 wk of AVP infusion, the rise in glycemia amounted to 1.1 mmol/l ( P < 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a V 1A R antagonist. Similar results were observed in lean Zucker rats. These findings demonstrate for the first time a causal link between chronic high AVP and hyperglycemia through V 1A R activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes., (Copyright © 2017 the American Physiological Society.)