Faculty Collaboration Database

Aberrant expression of S-SCAM causes the loss of GABAergic synapses in hippocampal neurons. Sci Rep 2020 Jan 09;10(1):83

Date

01/11/2020

Pubmed ID

31919468

Pubmed Central ID

PMC6952429

DOI

10.1038/s41598-019-57053-y

Scopus ID

2-s2.0-85077694386 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

The duplication and deletion mutations of the S-SCAM/MAGI-2 gene are associated with schizophrenia and infantile spasms, respectively. S-SCAM is a unique synaptic scaffolding protein that localizes to both excitatory and GABAergic synapses. However, consequences of aberrant S-SCAM expression on GABAergic synapses is little studied. Here we report the effect of S-SCAM knockdown and overexpression on GABAergic synapses. S-SCAM knockdown in cultured hippocampal neurons caused a drastic loss of both pre- and post-synaptic components of GABAergic synapses, indicating its essential role in GABAergic synapse formation and maintenance. Surprisingly, S-SCAM overexpression also attenuated GABAergic synapses, but the effect is mediated by the loss of postsynaptic GABA_A receptors, gephyrin, and neuroligin 2 and does not involve presynaptic component vesicular GABA transporters. Overexpression studies using S-SCAM mutants with various domain deletions indicated that GABAergic synapse loss correlates with their ability to increase excitatory synaptic function. Consistently, AMPA receptor antagonist CNQX or calcineurin inhibitor FK506 abolished the S-SCAM overexpression-induced loss of GABA_A receptors, supporting that GABAergic synapse loss by S-SCAM overexpression is due to the activity-induced dispersal of synaptic GABA_A receptors. These results suggest that abnormal S-SCAM protein levels disrupt excitation/inhibition balance in neurons, which may explain the pathogenic nature of S-SCAM copy number variations.

Author List

Shin SM, Skaar S, Danielson E, Lee SH

Author

Sang H. Lee PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Animals
Cells, Cultured
Embryo, Mammalian
Guanylate Kinases
Hippocampus
Neurons
Rats
Rats, Sprague-Dawley
Receptors, GABA-A
Synapses