Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5.

Abstract:

:Activation of postsynaptic metabotropic glutamate receptors (mGluRs) modulates neuronal excitability and synaptic plasticity, while deregulation of mGluR signaling has been implicated in neurodevelopmental disorders. Overstimulation of mGluRs is restricted by the rapid endocytosis of receptors after activation. However, how membrane trafficking of mGluRs at synapses is controlled remains poorly defined. We find that in hippocampal neurons, the agonist-induced receptor internalization of synaptic mGluR5 is significantly reduced in Shank knockdown neurons. This is rescued by the re-expression of wild-type Shanks, but not by mutants unable to bind Homer1b/c, Dynamin2, or Cortactin. These effects are paralleled by a reduction in synapses associated with an endocytic zone. Moreover, a mutation in SHANK2 found in autism spectrum disorders (ASDs) similarly disrupts these processes. On the basis of these findings, we propose that synaptic Shank scaffolds anchor the endocytic machinery to govern the efficient trafficking of mGluR5 and to balance the surface expression of mGluRs to efficiently modulate neuronal functioning.

journal_name

Cell Rep

journal_title

Cell reports

authors

Scheefhals N,Catsburg LAE,Westerveld ML,Blanpied TA,Hoogenraad CC,MacGillavry HD

doi

10.1016/j.celrep.2019.08.102

subject

Has Abstract

pub_date

2019-10-08 00:00:00

pages

258-269.e8

issue

2

issn

2211-1247

pii

S2211-1247(19)31164-7

journal_volume

29

pub_type

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