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Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is  CNTNAP2  encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan’s syndrome, and limbic encephalitis. Despite the clear implication of  CNTNAP2  and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression  in vitro  or  in vivo  decreases the synaptic expression of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling  in vitro  and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in  CNTNAP2  may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2