서판길 (Pann-Ghill Suh) UNIST
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Mol. Psychiatr., (2017) 22, 1473-1482 | doi: 10.1038/mp.2016.261
Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior

Y R Yang1,2,13, J H Jung3,13, S-J Kim3, K Hamada4, A Suzuki4, H J Kim3, J H Lee3, O-B Kwon3, Y K Lee5, J Kim6, E-K Kim1, H-J Jang1, D-S Kang1, J-S Choi5, C J Lee6, J Marshall7, H-Y Koh6, C-J Kim8, H Seok9, S H Kim10, J H Choi1, Y-B Choi11, L Cocco12, S H Ryu3, J-H Kim3,* and P-G Suh1,*

1
School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea
2Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
3Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
4Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
5Department of Psychology, Korea University, Seoul, Republic of Korea
6Center for Functional Connectomics, and Center for Neural Science, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
7Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, USA
8Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
9Department of Biomedical Engineering, Jungwon University, Goesan, Republic of Korea
10Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea
11Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY, USA
12Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

*Correspondence: Professor J-H Kim, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Life Sciences Building, Room 105, Cheongam-Ro 77, Nam-Gu, Pohang, Gyungbuk 37673, Republic of Korea; Professor P-G Suh, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Building 104, Room 705, UNIST-gil 50, Eonyang-eup, Ulsan 44919, Republic of Korea.

13
The first two authors contributed equally to this work.

Abstract
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Category: Molecular_Biology, Biochemistry, Neuroscience
등록일 2017.02.06
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