Autism‐associated Shank3 mutations alter mGluR expression and mGluR‐dependent but not NMDA receptor‐dependent long‐term depression
Synapse. 2019-03-23; 73(8): e22097
DOI: 10.1002/syn.22097
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Lee K(1), Vyas Y(1), Garner CC(2), Montgomery JM(1).
Author information:
(1)Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
(2)German Center for Neurodegenerative Disorders, Charité – Universitätsmedizin Berlin, Berlin, Germany.
SHANK3 is a postsynaptic structural protein localized at excitatory glutamatergic
synapses in which deletions and mutations have been implicated in patients with
autism spectrum disorders (ASD). The expression of Shank3 ASD mutations causes
impairments in ionotropic glutamate receptor-mediated synaptic responses in
neurons, which is thought to underlie ASD-related behaviors, thereby indicating
glutamatergic synaptopathy as one of the major pathogenic mechanisms. However,
little is known about the functional consequences of ASD-associated mutations in
Shank3 on another important set of glutamate receptors, group I metabotropic
glutamate receptors (mGluRs). Here, we further assessed how Shank3 mutations
identified in patients with ASD (one de novo InsG mutation and two inherited
point mutations, R87C and R375C) disrupt group I mGluR (mGluR1 and mGluR5)
expression and function. To identify potential isoform-specific deficits induced
by ASD-associated Shank3 mutations on group I mGluRs, we surface immunolabeled
mGluR1 and mGluR5 independently. We also induced mGluR-dependent synaptic
plasticity (R,S-3,5-dihydroxyphenylglycine [DHPG]-induced long-term depression
[LTD]) as well as N-methyl-D-aspartate receptor (NMDAR)-dependent LTD.
ASD-associated mutations in Shank3 differentially interfered with the ability of
cultured hippocampal neurons to express mGluR5 and mGluR1 at synapses.
Intriguingly, all ASD Shank3 mutations impaired mGluR-dependent LTD without
altering NMDAR-dependent LTD. Our data show that the specific perturbation in
mGluR-dependent synaptic plasticity occurs in neurons expressing ASD-associated
Shank3 mutations, which may underpin synaptic dysfunction and subsequent
behavioral deficits in ASD.
© 2019 Wiley Periodicals, Inc.