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The Cognitive Endophenotype of Neuropsychiatric Disorders: Evidence from Mouse Models Open Access

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Autism spectrum disorder is a neuropsychiatric condition characterized by abnormal interactions, communicative deficits, and perseverative thoughts and behaviors. In addition to these core symptoms, autism is associated with a cognitive endophenotype of spared and impaired executive abilities. People with other neuropsychiatric disorders like schizophrenia also show executive dysfunction. Intact executive function requires prefrontal cortex and its connections to other cortical areas. Measures of executive control in adults with neuropsychiatric disorders are predictive of adaptive functioning, so research should seek methods for minimizing these impairments. A helpful tool in this search is the laboratory mouse. Mice possess homologous prefrontal cortex and assays exist for quantifying rodent cognition. The core domains of autistic behavior can be evaluated in mice as well. Mouse models can therefore be used to investigate neuropsychiatric symptoms. BTBR, LgDel, and Cntnap2 mice are valid models of neuropsychiatric disorder. Using visual discrimination tasks presented in an automated operant touchscreen apparatus, three separate studies on these models were performed to determine the cognitive profiles of these mice. BTBR mice and C57 mice were assessed on a series of tasks. BTBR did not differ from C57 on the acquisition or reversal of the visual discrimination. They did, however, show deficits on a novel task that required contextual inhibition of a prepotent response. LgDel mice and wildtype littermates were tested on the visual discrimination acquisition and reversal. LgDel mice were impaired on one measure of the acquisition and several measures of reversal, including learning errors which is thought to depend on medial prefrontal cortical circuitry. Additionally, frequency of layer 2/3 projection neurons in this region significantly correlated with cognitive performance. Lastly, Cntnap2 null mice were compared on touchscreen tasks to wildtype and heterozygous littermates. Like LgDel, Cntnap2 null mice were impaired on a measure of acquisition and some reversal measures including learning errors. Separately, these studies contribute validation to the behavioral phenotypes of the three mouse models of neuropsychiatric and neurodevelopmental disorder. Together, they also provide evidence of the utility of computer-automated touchscreen systems for revealing subtle cognitive deficits that correlate with prefrontal cortical structures.

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