The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia

• DOI: 10.1073/pnas.0710717105
• Publication Date: 2008-04-15T01:10:43Z
• Authors: Mitsuyuki Matsumoto; Richard E. Straub; Stefano Marenco; Kristin K. Nicodemus; Shun-ichiro Matsu...; Akihiko Fujikawa; Sosuke Miyoshi; Miwako Shobo; Shinji Takahashi; Junko Yarimizu; Masatoshi Yuri; Masashi Hiramoto; Shuji Morita; Hiroyuki Yokota; Takeshi Sasayama; Kazuhiro Terai; Masayasu Yoshino; Akira Miyake; Joseph H. Callicott; Michael F. Egan; Andreas Meyer-Lin...; Lucas Kempf; Robyn Honea; Radha Krishna Vak...; Jun Takasaki; Masazumi Kamohara; Takatoshi Soga; Hideki Hiyama; Hiroyuki Ishii; Ayako Matsuo; Shintaro Nishimura; Nobuya Matsuoka; Masato Kobori; Hitoshi Matsushime; Masao Katoh; Kiyoshi Furuichi; Daniel R. Weinberger
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Behavior, Animal; Molecular Sequence Data; Brain; Nerve Tissue Proteins; Organ Size; Magnetic Resonance Imaging; Polymorphism, Single Nucleotide; Receptors, G-Protein-Coupled; 3. Good health; Evolution, Molecular; Mice; 03 medical and health sciences; Schizophrenia; Animals; Humans; Genetic Predisposition to Disease; Schizophrenic Psychology; Amino Acid Sequence; Alleles

The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3′ UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.