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Mol Psychiatry. 2017 Oct;22(10):1473-1482. doi: 10.1038/mp.2016.261. Epub 2017 Jan 31.

Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior.

Author information

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

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.

PMID:
28138157
DOI:
10.1038/mp.2016.261
[Indexed for MEDLINE]

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