title: Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior.
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.
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.|Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Y R
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: O-B
authors.initials: OB
authors.lastname: Kwon
authors.affiliation: Department of Psychology, Korea University, Seoul, Republic of Korea.
authors.forename: Y K
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Center for Functional Connectomics, and Center for Neural Science, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: E-K
authors.initials: EK
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: D-S
authors.initials: DS
authors.lastname: Kang
authors.affiliation: Department of Psychology, Korea University, Seoul, Republic of Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Center for Functional Connectomics, and Center for Neural Science, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors.forename: C J
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Center for Functional Connectomics, and Center for Neural Science, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Koh
authors.affiliation: Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Jungwon University, Goesan, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Seok
authors.affiliation: Department of Psychiatry, Dongguk University International Hospital, Goyang, Republic of Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Y-B
authors.initials: YB
authors.lastname: Choi
authors.affiliation: Cellular Signaling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cocco
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Ryu
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
authors.forename: P-G
authors.initials: PG
authors.lastname: Suh
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000201:enzymology* / Q000235:genetics* / Q000469:parasitology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D051966:Phospholipase C gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000201:enzymology* / Q000473:pathology; D017966:Pyramidal Cells / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D017447:Receptors, Dopamine D1; D013569:Synapses / Q000201:enzymology / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017447:Receptors, Dopamine D1; D005680:gamma-Aminobutyric Acid; D020813:Receptor, trkB; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse