The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons

Ruoqi Gao, Colleen R. Zaccard, Lauren P. Shapiro, Leonardo E. Dionisio, Maria Dolores Martin-de-Saavedra, Nicolas H. Piguel, Christopher P. Pratt, Katherine E. Horan, Peter Penzes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


GABAergic interneurons are emerging as prominent substrates in the pathophysiology of multiple neurodevelopmental disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and epilepsy. Interneuron excitatory activity is influenced by 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs), which in turn affects excitatory transmission in the central nervous system. Yet how dysregulation of interneuronal AMPARs distinctly contributes to the molecular underpinning of neurobiological disease is drastically underexplored. Contactin-associated protein-like 2 (CNTNAP2) is a neurexin-related adhesion molecule shown to mediate AMPAR subcellular distribution while calcium/calmodulin-dependent serine protein kinase (CASK) is a multi-functional scaffold involved with glutamate receptor trafficking. Mutations in both genes have overlapping disease associations, including autism spectrum disorders, intellectual disability, and epilepsy, thus suggesting converging perturbations of excitatory/inhibitory balance. Our lab has previously shown that CNTNAP2 stabilizes interneuron dendritic arbors through CASK and that CNTNAP2 regulates AMPAR subunit GluA1 trafficking in excitatory neurons. The interaction between these three proteins, however, has not been studied in interneurons. Using biochemical techniques, structured illumination microscopy (SIM) and shRNA technology, we first confirm that these three proteins interact in mouse brain, and then examined relationship between CNTNAP2, CASK and GluA1 in mature interneurons. Using SIM, we ascertain that a large fraction of endogenous CNTNAP2, CASK, and GluA1 molecules collectively colocalize together in a tripartite manner. Finally, individual knockdown of either CNTNAP2 or CASK similarly alter GluA1 levels and localization. These findings offer insight to molecular mechanisms underlying GluA1 regulation in interneurons.

Original languageEnglish (US)
Pages (from-to)92-99
Number of pages8
JournalNeuroscience Letters
StatePublished - May 14 2019


  • AMPA receptors
  • Autism spectrum disorders
  • Cntnap2
  • Dendrites
  • Excitatory-inhibitory balance
  • Language disorders
  • Mechanism
  • Neuropsychiatric disorders
  • Schizophrenia
  • Structured illumination microscopy

ASJC Scopus subject areas

  • Neuroscience(all)

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