Caspr2 interacts with type 1 inositol 1,4,5-trisphosphate receptor in the developing cerebellum and regulates Purkinje cell morphology

Liam Argent,Friederike Winter,Imogen Prickett,Maria Carrasquero-Ordaz,Abby L Olsen,Holger Kramer,Eric Lancaster,Esther B.E Becker

doi:10.1074/jbc.ra120.012655

Abstract

Contactin-associated protein-like 2 (Caspr2) is a neurexin-like protein that has been associated with numerous neurological conditions. However, the specific functional roles that Caspr2 plays in the central nervous system and their underlying mechanisms remain incompletely understood. Here, we report on a functional role for Caspr2 in the developing cerebellum. Using a combination of confocal microscopy, biochemical analyses, and behavioral testing, we show that loss of Caspr2 in the Cntnap2−/− knockout mouse results in impaired Purkinje cell dendritic development, altered intracellular signaling, and motor coordination deficits. We also find that Caspr2 is highly enriched at synaptic specializations in the cerebellum. Using a proteomics approach, we identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 extracellular domain in the molecular layer of the developing cerebellum. The interaction of the Caspr2 extracellular domain with IP3R1 inhibits IP3R1-mediated changes in cellular morphology. Together, our work defines a mechanism by which Caspr2 controls the development and function of the cerebellum and advances our understanding of how Caspr2 dysfunction might lead to specific brain disorders.

Highlights

Contactin-associated protein-like 2 (Caspr2) is a neurexinlike protein that has been associated with numerous neurological conditions
Caspr2 protein was highly expressed in the mouse cerebellum from the second week of postnatal development (Fig. 1A), which coincides temporally with the outgrowth of Purkinje cell dendrites and synapse development in the cerebellar cortex [17]
We found that the phosphorylation status and the activity of the extracellular-regulated kinases 1/2 (ERK1/2) was reduced in Cntnap2 KO mice compared with WT littermates, consistent with altered intracellular signaling in the absence of Caspr2 (Fig. 4, C and D)

Summary

Introduction

Contactin-associated protein-like 2 (Caspr2) is a neurexinlike protein that has been associated with numerous neurological conditions. Mutant mice lacking Cntnap2 show distinct cerebellum-associated behavioral impairments and abnormal Purkinje cell development. We identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 ECD in the molecular layer (ML) of the developing cerebellum.

Results

Conclusion