Abstract
SummaryActivation 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.
Highlights
At excitatory synapses of hippocampal neurons, the group I metabotropic glutamate receptors mGluR1 and mGluR5 critically modulate synaptic transmission and plasticity (Scheefhals and MacGillavry, 2018)
We found that agonist-induced internalization of mGluR5 is severely affected in Shank triple knockdown neurons and present evidence that mGluR5 is internalized through the endocytic zones (EZs) coupled to the postsynaptic density (PSD) by Shank-mediated interactions
Efficient Internalization and Intracellular Sorting of Activated mGluR5 To test whether the activation of mGluR5 triggers endocytosis in hippocampal neurons, we live-labeled surface-expressed myc-mGluR5, and incubated neurons with the group I-specific agonist (S)-3,5-dihydroxyphenylglycine (DHPG)
Summary
At excitatory synapses of hippocampal neurons, the group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 critically modulate synaptic transmission and plasticity (Scheefhals and MacGillavry, 2018). Despite the importance of controlled receptor trafficking at synapses, we know little about the mechanisms that control the endocytosis and recycling of synaptic mGluRs. The endocytosis of postsynaptic membrane proteins preferentially takes place at endocytic zones (EZs) (Rosendale et al, 2017). EZs are stable clathrin assemblies coupled to the postsynaptic density (PSD) via interactions with Homer1b/c and Dynamin (Blanpied et al, 2002; Lu et al, 2007; Racz et al, 2004). Disruption of the PSD-EZ coupling reduces the synaptic population of the a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPARs), and prevents plasticity-induced receptor insertion (Petrini et al, 2009). Whether mGluRs are locally endocytosed through EZs and recycle to the synaptic membrane remains untested
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