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

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

Cognitive impact of neuronal antibodies: encephalitis and beyond

“…Finally, CASPR2-antibodies may also exert their pathogenicity by altering the protein's known function in AMPAR synaptic traffic. A recent study showed significant synaptic loss of AMPARs in cortical neurons incubated with IgG1 and IgG4 CASPR2 antibodies, while in vivo injection of the same antibodies in the mouse visual cortex significantly decreased AMPAR-mediated currents 67 .…”

“…Components of this figure were created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com . The shapes of the electrophysiological traces were modelled on data published in 47 , 61 , 147 . …”

“…The role of CASPR2 at the CNS synapse, however, is not well known, but the bulk of data suggests important functions in synaptic processes and neuronal activity. CASPR2 was implicated in the trafficking of AMPA receptors to the synaptic membrane 60 , 61 , suggesting that glutamatergic transmission dysfunction could underpin the cognitive impairment seen in CASPR2-mediated CNS disease. Others suggest that CASPR2 has a role in inhibitory hippocampal synapses, and that the antibody-mediated perturbation of inhibitory interneuron activity could lead to increased neuronal hyperexcitability and ultimately to the seizures suffered by these patients 62 , 63 .…”

In vivo Mechanisms of Antibody-Mediated Neurological Disorders: Animal Models and Potential Implications

“…Injection of a mixture of CASPR2-Abs in mouse visual cortex produced impaired localization of mouse Caspr2 to excitatory synapses and significantly decreased AMPAR-mediated currents in layer 2/3 pyramidal neurons; this implied a dysfunction of glutamatergic transmission in the pathogenesis of CASPR2-Ab encephalitis (52). Future studies should evaluate in parallel the effects of CASPR2-Abs on its partner protein network and on neuronal activity.…”

Analyzing the Potential Biological Determinants of Autism Spectrum Disorders: From Neuroinflammation to Kynurenines Pathway

“…Today, numerous autism-related proteins have been identified and are object of intensive research efforts in order to understand the phenotypic risks for autism. Examples are MeCP2 protein [ 7 ], reelin protein [ 8 ], CASPR2 protein [ 9 ] and CNTNAP2 protein [ 10 ]. Immune activation and prenatal exposure to toxins such as thalidomide and valproic acid have been considered environmental factors contributing to idiopathic ASD [ 11 ].…”