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Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism
Abstract
Background Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt(-/-)) and the OT receptor null mice (Oxtr(-/-)) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization.Methods Oxtr(-/-) mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr(+/+) and Oxtr(-/-) mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography.Results Oxtr(-/-) mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA-ergic versus total presynapses in hippocampal neurons of Oxtr(-/-) mice.Conclusions Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr(-/-) adult animals. The Oxtr(-/-) mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention.
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In the citing paper
“In OTR null mice social exploration and social recognition are reduced, while aggression is increased when compared to wild-type mice.”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [53]
In the citing paper
“While intracerebroventricular (ICV) injection of OT or AVP can restore wild-type levels of these behaviors, the effects of OT and AVP are inhibited by a selective V1aR antagonist.”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [53]
In the citing paper
“There are also studies that have found that OT can act via V1aRs to influence a range of social behaviors [53].”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [53]
In the citing paper
“as discussed above, a V1aR antagonist inhibits the ability of OT to increase social recognition in OTR knock-out mice [53].”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [53]
In the citing paper
“The neuropeptide oxytocin (OXT) has been strongly implicated in social behaviors including social recognition, social approach, pair bonding, paternal care and maternal behavior (Lim et al, 2005;Sala et al, 2011;Winslow and Insel, 2002).”
From Chronic and acute intranasal oxytocin produce divergent social effects in mice (2014) · cites this paper as Sala et al, 2011
In the citing paper
“an acute intracerebroventricular injection of OXT in wild-type male mice reduced the sociability towards a stranger male subject (Sala et al, 2011).”
From Chronic and acute intranasal oxytocin produce divergent social effects in mice (2014) · cites this paper as Sala et al, 2011
In the citing paper
“Therefore, administering oxytocin (for example, in the form of a nasal spray), or other substances that enhance central oxytocin turnover might be effective in ASD even in the presence of a disrupted oxytocin system [164].”
From Social “wanting” dysfunction in autism: neurobiological underpinnings and treatment implications (2012) · cites this paper as [210]
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Metadata
- Authors
- Sala, M., Braida, D., Lentini, D., Busnelli, M., Bulgheroni, E., Capurro, V., Finardi, A., Donzelli, A., Pattini, L., Rubino, T., Parolaro, D., Nishimori, K., Parenti, M., & Chini, B.
- Affiliations
- University of Milan (IT)
- University of Milano-Bicocca (IT)
- National Research Council (IT)
- Politecnico di Milano (IT)
- University of Insubria (IT)
- Tohoku University (JP)
- Corresponding author
- Chini, Bice
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 69
- Issue
- 9
- Pages
- 875-882
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2116573486
- Cited by
- 375
- References
- 61
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 15 · 2023: 18 · 2022: 19 · 2021: 24 · 2020: 23 · 2019: 19 · 2018: 33 · 2017: 31 · 2016: 33 · 2015: 32 · 2014: 26 · 2013: 21 · 2012: 35
- FWCI
- 42.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- Virtual Community of Pathological Anatomy (University of Castilla La Mancha) (submittedVersion)
- Funders
- Fondazione Cariplo
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, oxytocin, oxytocin receptor, vasopressin, vasopressin V1a receptor, social behavior, aggression, seizure susceptibility, cognitive flexibility, social novelty, GABAergic synapses, glutamatergic synapses, hippocampus
- MeSH terms
- Aggression, Analysis of Variance, Animals, Arginine Vasopressin, Autistic Disorder, Autoradiography, Cells, Cultured, Cognition, Disease Models, Animal, Hippocampus, Immunohistochemistry, Male, Neurons, Oxytocin, Seizures, Social Behavior, Receptors, Oxytocin, Mice, Knockout, Mice
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