Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes.
BACKGROUND
We previously performed systematic association studies of glutamate receptor gene family members with schizophrenia, and found positive associations of polymorphisms in the GRM3 (a gene of metabotropic glutamate receptor 3: mGluR3) with the disorder. Physiological roles of GRM3 in brain functions and its functional roles in the pathogenesis of schizophrenia remain to be resolved.


RESULTS
We generated mGluR3 knockout (KO) mice and conducted comprehensive behavioral analyses. KO mice showed hyperactivity in the open field, light/dark transition, and 24-hour home cage monitoring tests, impaired reference memory for stressful events in the Porsolt forced swim test, impaired contextual memory in cued and contextual fear conditioning test, and impaired working memory in the T-Maze forced alternation task test. Hyperactivity and impaired working memory are known as endophenotypes of schizophrenia. We examined long-term synaptic plasticity by assessing long-term potentiation (LTP) in the CA1 region in the hippocampi of KO and wild-type (WT) mice. We observed no differences in the amplitude of LTP between the two genotypes, suggesting that mGluR3 is not essential for LTP in the CA1 region of the mouse hippocampus. As hyperactivity is typically associated with increased dopaminergic transmission, we performed in vivo microdialysis measurements of extracellular dopamine in the nucleus accumbens of KO and WT mice. We observed enhancements in the methamphetamine (MAP)-induced release of dopamine in KO mice.


CONCLUSIONS
These results demonstrate that a disturbance in the glutamate-dopamine interaction may be involved in the pathophysiology of schizophrenia-like behavior, such as hyperactivity in mGluR3 KO mice.
Ryuta
R
Fujioka
Takenobu
T
Nii
Akiko
A
Iwaki
Atsushi
A
Shibata
Isao
I
Ito
Kiyoyuki
K
Kitaichi
Masatoshi
M
Nomura
Satoko
S
Hattori
Keizo
K
Takao
Tsuyoshi
T
Miyakawa
Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of Bioregulation, Fukuoka 812-8582, Japan. yfukumak@gen.kyushu-u.ac.jp.
Yasuyuki
Y
Fukumaki
D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D058068:Endophenotypes / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D005684:Gait / Q000502:physiology; D006624:Hippocampus / Q000503:physiopathology; D007266:Inhibition, Psychological; D017774:Long-Term Potentiation / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009714:Nucleus Accumbens / Q000503:physiopathology; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency* / Q000378:metabolism; D013216:Reflex, Startle / Q000502:physiology; D012559:Schizophrenia / Q000473:pathology* / Q000503:physiopathology; D012919:Social Behavior; D013550:Swimming; D013647:Task Performance and Analysis
D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D004298:Dopamine