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A Novel Vasopressin V1a Antagonist Restores Social Behavior in the Mouse Cntnap2 KO Model of Autism

Thursday, May 10, 2018: 11:30 AM-1:30 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
C. Grundschober1, A. Genet1, M. Saxe1, P. Schnider2 and B. Biemans1, (1)Neuroscience Discovery, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland, (2)Medicinal Chemistry, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
Background: The neuropeptide vasopressin is mainly produced in the lateral hypothalamus and plays an important role in regulating aggressive and social behavior by activating the V1a vasopressin receptor. A missense mutation in the human contactin-associated protein-like 2 (CNTNAP2) gene has been identified in an Amish family, leading to cortical dysplasia–focal epilepsy (CDFE) syndrome. Out of the 9 originally reported cases, 6 have autism. CNTNAP2 is a cell adhesion molecule, important for AMPA receptor trafficking, development of dendritic arborization, and stabilization of dendritic spines. Cntnap2 knockout mice (Cntnap2 KO) demonstrate reduced social behavior and increased repetitive behavior (grooming).

Objectives: Investigate the effect of central V1a receptor blockade on the phenotype of the mouse Cntnap2 KO model of autism.

Methods: Cntnap2 KO mice were treated daily during 3 weeks with a novel brain penetrant V1a receptor-specific small molecule antagonist, starting at postnatal day 40. Social behavior and self-grooming was assessed during a direct social interaction test at P48. Self-grooming was measured again in a single setting at P52, and locomotor activity was assessed at P62.

Results: At postnatal day 48, chronic treatment with our V1a receptor-specific small molecule antagonist completely reversed the impairment in social behavior seen in Cntnap2 KO at 15 and 30 mg/kg i.p., which are doses predicted to block 77 to 88% of brain V1a receptors. The exaggerated grooming was also reduced at the highest dose tested (60 mg/kg i.p). None of the tested doses affected locomotor activity at P62.

Conclusions: Our data show that sub-chronic inhibition of vasopressin V1a receptors restores normal social behavior in Cntnap2 KO mice. The effect on repetitive behavior is only apparent at the highest tested dose, suggesting that grooming is either less sensitive to V1a inhibition or not directly mediated by V1a activation. Further experiments will be needed to clarify this finding.

These results suggest that V1a antagonists have the potential to improve social interaction in autism, a core symptom for which there is currently no drug treatment.

See more of: Animal Models
See more of: Animal Models