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

Mitsuyuki Matsumoto, Richard E. Straub, Stefano Marenco, Kristin K Nicodemus, Shun-Ichiro Matsumoto, 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 EganAndreas Meyer-Lindenberg, Lucas Kempf, Robyn Honea, Radha Krishna Vakkalanka, 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)6133-8
Number of pages6
JournalProceedings of the National Academy of Sciences
Issue number16
Publication statusPublished - 22 Apr 2008


  • Alleles
  • Amino Acid Sequence
  • Animals
  • Behavior, Animal
  • Brain
  • Evolution, Molecular
  • Genetic Predisposition to Disease
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Organ Size
  • Polymorphism, Single Nucleotide
  • Receptors, G-Protein-Coupled
  • Schizophrenia
  • Schizophrenic Psychology
  • Journal Article


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