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16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors.

ABSTRACT: In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). As ASD is frequently associated with altered response to acute stress and stress may exacerbate repetitive behavior in ASD, we studied the Del mouse behavior in the context of an acute stress using the forced swim test, a paradigm well characterized with respect to serotonin. Del mice perseverated with active coping (swimming) in the forced swim test and failed to adopt passive coping strategies with time as did their wild-type littermates. Analysis of monoamine content by HPLC provided evidence for altered endogenous serotonin neurotransmission in Del mice while there was no effect of genotype on any other monoamine. Moreover, we found that Del mice were highly sensitive to the 5-HT2A antagonists M100907, which at a dose of 0.1 mg/kg normalized their level of active coping and restored the gradual shift to passive coping in the forced swim test. Supporting evidence for altered endogenous serotonin signaling was provided by observations of additional ligand effects including altered forebrain Fos expression. Taken together, these observations indicate notable changes in endogenous serotonin signaling in 16p11.2 deletion mice and support the therapeutic utility of 5-HT2A receptor antagonists.

SUBMITTER: Panzini CM

PROVIDER: S-EPMC5729115 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors.

Panzini Chris M CM Ehlinger Daniel G DG Alchahin Adele M AM Guo Yueping Y Commons Kathryn G KG

Journal of neurochemistry 20171110 6

In humans a chromosomal hemideletion of the 16p11.2 region results in variable neurodevelopmental deficits including developmental delay, intellectual disability, and features of autism spectrum disorder (ASD). Serotonin is implicated in ASD but its role remains enigmatic. In this study we sought to determine if and how abnormalities in serotonin neurotransmission could contribute to the behavioral phenotype of the 16p11.2 deletion syndrome in a mouse model (Del mouse). As ASD is frequently asso ...[more]

PMID: 28948999

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Project description:Background22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition associated to a high risk for psychiatric disorders, including psychosis. Individuals with 22q11DS are thought to experience increased levels of chronic stress, which could lead to alterations in hypothalamic-pituitary-adrenocortical (HPA)-axis functioning. In the current study, we investigated for the first time diurnal salivary cortisol profiles in adolescents and young adults with 22q11DS as well as their link with stress exposure, coping strategies and psychopathology, including psychotic symptoms.MethodsSalivary cortisol was collected from adolescents and young adults with 22q11DS (n = 30, age = 19.7) and matched healthy controls (HC; n = 36, age = 18.5) six times a day for two days. Exposure to stressful life events, including peer victimization, coping strategies and general psychopathology were assessed with questionnaires. Psychotic symptoms and psychiatric comorbidities were evaluated with clinical interviews.ResultsWe observed similar daily levels and diurnal profiles of salivary cortisol in adolescents and young adults with 22q11DS compared to HCs. However, participants with 22q11DS reported less frequent exposure to stress than HCs. In 22q11DS, we observed a significant association between the use of non-adaptive coping strategies and the severity of psychotics symptoms. Cortisol level was not associated to severity of psychotic symptoms, but elevated cortisol awakening response (CAR) was found in participants with 22q11DS with higher levels of general psychopathology.ConclusionsOur results do not support earlier propositions of altered HPA-axis functioning in 22q11DS but highlight the need to further investigate diurnal cortisol as an indicator of HPA-axis functioning and its link with (earlier) stress exposure and psychopathology in this population. Interventions should target the development of adaptive coping skills in preventing psychosis in 22q11DS.

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16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors.

Publications

16p11.2 deletion syndrome mice perseverate with active coping response to acute stress - rescue by blocking 5-HT2A receptors.

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