RT Journal Article
T1 Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons
A1 Varea, Olga
A1 Martín De Saavedra Álvarez De Uribarri, María Dolores
A1 Kopeikina, Katherine J.
A1 Schürmann, Britta
A1 Fleming, Hunter J.
A1 Fawcett-Patel, Jessica M.
A1 Bach, Anthony
A1 Jang, Seil
A1 Peles, Elior
A1 Kim, Eunjoon
A1 Penzes, Peter
AB Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.
PB National Academy of Sciences
SN 0027-8424
YR 2015
FD 2015
LK https://hdl.handle.net/20.500.14352/93464
UL https://hdl.handle.net/20.500.14352/93464
LA eng
NO Varea O, Martin-de-Saavedra MD, Kopeikina KJ, Schürmann B, Fleming HJ, Fawcett-Patel JM, et al. Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2 /Caspr2 knockout neurons. Proc Natl Acad Sci USA 2015;112:6176–81. https://doi.org/10.1073/pnas.1423205112.
NO National Institute of Mental Health
NO Institute for Basic Science
NO German Research Foundation
NO Northwestern University
NO National Cancer Institute 
DS Docta Complutense
RD 10 abr 2025