Presenting Author:

M. Dolores Martin-de-Saavedra

Principal Investigator:

Peter Penzes, Ph.D.

Department:

Physiology

Keywords:

CNTNAP2, caspr2, ectodomain shedding, autism, epilepsy, intellectual disability, NR2B, calcium signalling, neuron, dendritic spine

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B166 - Basic Science

Implication of CNTNAP2 paracrine signaling for neurodevelopmental disorders

The CNTNAP2 gene is a risk factor for a complex range of phenotypes whose shared common features are intellectual disability, seizures, language impairments and autism spectrum disorder. CNTNAP2 encodes the CNTNAP2 or Caspr2 transmembrane protein which belongs to the neurexin superfamily. CNTNAP2 KO mice showed repetitive/restrictive behaviors, impaired communication and decreased social interaction. However, little is known about how CNTNAP2 contributes to the physiopathology of neurodevelopmental disorders. We and others have recently shown that CNTNAP2 is present at spiny synapses in excitatory cortical neurons, and is required for correct trafficking of GluA1 subunits of AMPA receptors and spine maintenance. We therefore set out to investigate its functions at synapses using a wide range of imaging techniques (including confocal and super resolution imaging), biochemistry and mass spectroscopy. We found that CNTNAP2 undergoes activity-dependent ectodomain shedding mediated by matrix metalloproteases. Using structured illumination microscopy we determined the subcellular sites of Cntnap2 ectodomain shedding. Incubation with Cntnap2 ectodomain promotes morphological and functional changes in cortical neurons. Proteomics analysis has identified novel candidate binding partners of CNTNAP2 ectodomain. Taken together, our findings can provide new insight into the role of CNTNAP2 at synapses and in the pathogenesis of neurodevelopmental disorders.