Faculty Collaboration Database

S-SCAM, a rare copy number variation gene, induces schizophrenia-related endophenotypes in transgenic mouse model. J Neurosci 2015 Feb 04;35(5):1892-904

Date

02/06/2015

Pubmed ID

25653350

Pubmed Central ID

PMC4315826

DOI

10.1523/JNEUROSCI.3658-14.2015

Scopus ID

2-s2.0-84922355999 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

Accumulating genetic evidence suggests that schizophrenia (SZ) is associated with individually rare copy number variations (CNVs) of diverse genes, often specific to single cases. However, the causality of these rare mutations remains unknown. One of the rare CNVs found in SZ cohorts is the duplication of Synaptic Scaffolding Molecule (S-SCAM, also called MAGI-2), which encodes a postsynaptic scaffolding protein controlling synaptic AMPA receptor levels, and thus the strength of excitatory synaptic transmission. Here we report that, in a transgenic mouse model simulating the duplication conditions, elevation of S-SCAM levels in excitatory neurons of the forebrain was sufficient to induce multiple SZ-related endophenotypes. S-SCAM transgenic mice showed an increased number of lateral ventricles and a reduced number of parvalbumin-stained neurons. In addition, the mice exhibited SZ-like behavioral abnormalities, including hyperlocomotor activity, deficits in prepulse inhibition, increased anxiety, impaired social interaction, and working memory deficit. Notably, the S-SCAM transgenic mice showed a unique sex difference in showing these behavioral symptoms, which is reminiscent of human conditions. These behavioral abnormalities were accompanied by hyperglutamatergic function associated with increased synaptic AMPA receptor levels and impaired long-term potentiation. Importantly, reducing glutamate release by the group 2 metabotropic glutamate receptor agonist LY379268 ameliorated the working memory deficits in the transgenic mice, suggesting that hyperglutamatergic function underlies the cognitive functional deficits. Together, these results contribute to validate a causal relationship of the rare S-SCAM CNV and provide supporting evidence for the rare CNV hypothesis in SZ pathogenesis. Furthermore, the S-SCAM transgenic mice provide a valuable new animal model for studying SZ pathogenesis.

Author List

Zhang N, Zhong P, Shin SM, Metallo J, Danielson E, Olsen CM, Liu QS, Lee SH

Authors

Sang H. Lee PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Christopher M. Olsen PhD Associate 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
Amino Acids
Animals
Anxiety
Bridged Bicyclo Compounds, Heterocyclic
DNA Copy Number Variations
Excitatory Postsynaptic Potentials
Female
Glutamic Acid
Guanylate Kinases
Locomotion
Long-Term Potentiation
Male
Maze Learning
Memory, Short-Term
Mice
Neurons
Parvalbumins
Phenotype
Prosencephalon
Receptors, AMPA
Schizophrenia
Sex Factors
Social Behavior
Up-Regulation