Objectives: Behavioral and neuropathological characterization of the Cntnap2 knockout mice as a potential mouse model for ASD.
Methods: Ten Cntnap2 knockout mice and wildtype littermates were evaluated in a broad battery of behavioral tests relevant to ASD (Silverman, 2010). Immunohistochemistry and electrophysiological studies were performed in three mice per genotype using conventional methods.
Results: Cntnap2 knockout mice recapitulate features observed in patients with idiopathic autism including abnormal vocal communication, repetitive and restrictive behaviors, and abnormal social interactions. In addition, they show hyperactivity and epileptic seizures, as has been reported in humans with CDFE syndrome. Neuropathologically, we observe defects in the migration of cortical projection neurons and a reduction in the number of GABAergic interneurons, which is accompanied by an imbalanced excitatory/inhibitory network. These data show that CNTNAP2 is involved in the development of cortical circuits, and further support alterations in excitatory-inhibitory balance in ASD pathophysiology. In addition, treating Cntnap2 knockout mice with risperidone, an antipsychotic drug approved for autism treatment by the FDA, rescues the repetitive behavior, but not the social deficits, a dissociation similar to what is seen in human patients.
Conclusions: These data demonstrate the validity of the Cntnap2 knockout as a mouse model for ASD and provide initial insight into the underlying mechanisms by which CNTNAP2 affects brain development and function, being an excellent tool for further studies to unravel ASD pathophysiology and for therapeutic research.
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See more of: Biological Mechanisms