title: Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1.
abstract: Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here, we show that ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits in ctoNrg1 mice require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Yin
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: Lu
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Bean
authors.forename: Anupama
authors.initials: A
authors.lastname: Sathyamurthy
authors.forename: Chengyong
authors.initials: C
authors.lastname: Shen
authors.forename: Xihui
authors.initials: X
authors.lastname: Liu
authors.forename: Thiri W
authors.initials: TW
authors.lastname: Lin
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Smith
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology; D014018:Tissue Distribution
chemical_list: D020890:Neuregulin-1; D018698:Glutamic Acid