title: The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia.
abstract: 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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. mitsuyuki.matsumoto@jp.astellas.com
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
authors.forename: Stefano
authors.initials: S
authors.lastname: Marenco
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Nicodemus
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Fujikawa
authors.forename: Sosuke
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Miwako
authors.initials: M
authors.lastname: Shobo
authors.forename: Shinji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Junko
authors.initials: J
authors.lastname: Yarimizu
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yuri
authors.forename: Masashi
authors.initials: M
authors.lastname: Hiramoto
authors.forename: Shuji
authors.initials: S
authors.lastname: Morita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yokota
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sasayama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Terai
authors.forename: Masayasu
authors.initials: M
authors.lastname: Yoshino
authors.forename: Akira
authors.initials: A
authors.lastname: Miyake
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egan
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.forename: Lucas
authors.initials: L
authors.lastname: Kempf
authors.forename: Robyn
authors.initials: R
authors.lastname: Honea
authors.forename: Radha Krishna
authors.initials: RK
authors.lastname: Vakkalanka
authors.forename: Jun
authors.initials: J
authors.lastname: Takasaki
authors.forename: Masazumi
authors.initials: M
authors.lastname: Kamohara
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Hideki
authors.initials: H
authors.lastname: Hiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishii
authors.forename: Ayako
authors.initials: A
authors.lastname: Matsuo
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nishimura
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Masato
authors.initials: M
authors.lastname: Kobori
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Matsushime
authors.forename: Masao
authors.initials: M
authors.lastname: Katoh
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Furuichi
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology*; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D012565:Schizophrenic Psychology
chemical_list: C416227:GPR85 protein, human; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; C528686:SREB2 protein, mouse