4.6 Article

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

期刊

CEREBRAL CORTEX
卷 29, 期 12, 页码 4919-4931

出版社

OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhz032

关键词

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

资金

  1. European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project BrainHealth 2020 [CENTRO-01-0145-FEDER-000008]
  2. European Regional Development Fund (ERDF) through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation
  3. Portuguese national funds via FCT-Fundacao para a Ciencia e a Tecnologia, I.P.
  4. FCT Portugal [POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-PTDC/SAU-NMC/4888/2014, POCI-01-0145-FEDER-29452, SFRH/BD/51682/2011]
  5. Fundação para a Ciência e a Tecnologia [SFRH/BD/51682/2011] Funding Source: FCT
  6. MRC [G0401222, G0501898] Funding Source: UKRI

向作者/读者索取更多资源

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 alpha-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.

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