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

Dominique Fernandes, Sandra D. Santos, Ester Coutinho, Jessica L. Whitt, Nuno Beltrão, Tiago Rondão, M. Isabel Leite, Camilla Buckley, Hey Kyoung Lee, Ana Luísa Carvalho

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4919-4931
Number of pages13
JournalCerebral Cortex
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2019

Keywords

  • AMPA receptors
  • Autoantibodies
  • CNTNAP2/CASPR2
  • experience-dependent plasticity
  • homoeostatic synaptic scaling
  • neuropsychiatric disorders

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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