PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function

Yuanyuan Wang,Meghan Kerrisk Campbell,Oded Foreman,Morgan Sheng,Jesse E Hanson,Irene Tom

doi:10.1038/s41598-020-67831-8

Abstract

The N-terminal domain (NTD) of the GluN1 subunit (GluN1-NTD) is important for NMDA receptor structure and function, but the interacting proteins of the GluN1-NTD are not well understood. Starting with an unbiased screen of ~ 1,500 transmembrane proteins using the purified GluN1-NTD protein as a bait, we identify Protocadherin 7 (PCDH7) as a potential interacting protein. PCDH7 is highly expressed in the brain and has been linked to CNS disorders, including epilepsy. Using primary neurons and brain slice cultures, we find that overexpression and knockdown of PCDH7 induce opposing morphological changes of dendritic structures. We also find that PCDH7 overexpression reduces synaptic NMDA receptor currents. These data show that PCDH7 can regulate dendritic spine morphology and synaptic function, possibly via interaction with the GluN1 subunit.

Highlights

The N-terminal domain (NTD) of the GluN1 subunit (GluN1-NTD) is important for NMDA receptor structure and function, but the interacting proteins of the GluN1-NTD are not well understood
We find that Pcdh[7] gene expression is colocalized with Grin[1] in neurons and find Protocadherin 7 (PCDH7) enriched in postsynaptic densities (PSDs)
Unbiased screen for GluN1-NTD binding partners. (A) left, one representative plate showing results from expression cloning screen with a library of ~ 1,500 single pass transmembrane proteins testing for binding to the purified NTD of GluN1 tagged with human-Fc

Summary

Introduction

The N-terminal domain (NTD) of the GluN1 subunit (GluN1-NTD) is important for NMDA receptor structure and function, but the interacting proteins of the GluN1-NTD are not well understood. We find that PCDH7 overexpression reduces synaptic NMDA receptor currents These data show that PCDH7 can regulate dendritic spine morphology and synaptic function, possibly via interaction with the GluN1 subunit. The N-terminal domain (NTD) of GluN1 has been reported to regulate NMDAR subunit oligomerization and assembly[10]. EphB receptors have been reported to bind GluN1-NTD and regulate excitatory synapse formation via this interaction[12]. Non-clustered protocadherins (PCDHδ family) are predominantly expressed in the nervous system, and multiple members from this group have been shown to modulate axon/dendrite structure and function and have been reported to be possibly related to human neurological disorders[15,16,17]. All the data point to a potential role of PCDH7 in the brain and perhaps in synapses, but the underlying mechanisms remain to be elucidated

Methods

Results

Conclusion