The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia.
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.
Matsumoto
Mitsuyuki
M
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan. mitsuyuki.matsumoto@jp.astellas.com
Straub
Richard E
RE
Marenco
Stefano
S
Nicodemus
Kristin K
KK
Matsumoto
Shun-Ichiro
S
Fujikawa
Akihiko
A
Miyoshi
Sosuke
S
Shobo
Miwako
M
Takahashi
Shinji
S
Yarimizu
Junko
J
Yuri
Masatoshi
M
Hiramoto
Masashi
M
Morita
Shuji
S
Yokota
Hiroyuki
H
Sasayama
Takeshi
T
Terai
Kazuhiro
K
Yoshino
Masayasu
M
Miyake
Akira
A
Callicott
Joseph H
JH
Egan
Michael F
MF
Meyer-Lindenberg
Andreas
A
Kempf
Lucas
L
Honea
Robyn
R
Vakkalanka
Radha Krishna
RK
Takasaki
Jun
J
Kamohara
Masazumi
M
Soga
Takatoshi
T
Hiyama
Hideki
H
Ishii
Hiroyuki
H
Matsuo
Ayako
A
Nishimura
Shintaro
S
Matsuoka
Nobuya
N
Kobori
Masato
M
Matsushime
Hitoshi
H
Katoh
Masao
M
Furuichi
Kiyoshi
K
Weinberger
Daniel R
DR
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
C416227:GPR85 protein, human; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; C528686:SREB2 protein, mouse