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Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and

Garret R Anderson1, Timothy Galfin, Wei Xu

  • 1Department of Molecular and Cellular Physiology, Nancy Pritzker Laboratory, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 18, 2012
PubMed

Insights

Contactin-associated protein 2 (CASPR2) is essential for neural circuit assembly. Its knockdown impairs neuron development, impacting synapse formation and function, crucial for autism spectrum disorder (ASD) pathogenesis.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Mutations in the contactin-associated protein 2 (CNTNAP2) gene, encoding CASPR2, are linked to autism spectrum disorder (ASD).
  • The precise function of CASPR2 in the assembly of neural circuits is not well understood.
  • CASPR2 is known to organize microdomains in mature myelinated axons.

Purpose of the Study:

  • To investigate the role of CASPR2 in neural network development.
  • To elucidate the cell-autonomous functions of CASPR2 in developing neurons.
  • To understand CASPR2's contribution to the pathogenesis of autism spectrum disorder.

Main Methods:

  • RNA interference (RNAi)-mediated knockdown of CASPR2 in neurons.
  • Assessment of dendritic arborization and spine development in pyramidal neurons.
  • Quantification of excitatory and inhibitory synapse numbers and synaptic transmission.

Main Results:

  • CASPR2 knockdown led to reduced dendritic arborization and spine density in pyramidal neurons.
  • A global decrease in both excitatory and inhibitory synapse numbers was observed.
  • Synaptic transmission decreased without alterations in synapse properties.

Conclusions:

  • CASPR2 plays a critical, cell-autonomous role in early neural circuit assembly.
  • This function in developing neurons is essential for normal neural network formation.
  • CASPR2's role in early development is critical during the time of autism spectrum disorder pathogenesis.

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