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.
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This work was supported by a National Research Foundation of Korea (NRF) Grant, funded by the Korean Government (MOE) (2013R1A1A2064434) and a grant by the Korean Government (MSIP) (2010-0028684 and 2007-341-C00027; to P-GS), and by NRF Grants (2014051826, 2015R1A2A1A15054037 and 2015M3C7A1027351; to J-HK). We thank MP Kong at POSTECH for supporting generation of PLCγ1 conditional knockout mice, YH Lee at UNIST for maintaining mice and technical support, JH Hur at UNIST-Olympus Biomedical imaging Center (UOBC) for technical support and M Suh at the Korea Institute of Science and Technology (KIST) for experimental support for the behavior test. We also thank CH Bailey (Neuroscience, Columbia University) for critical reading and comments.
The authors declare no conflict of interest.
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Yang, Y., Jung, J., Kim, SJ. et al. Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior. Mol Psychiatry 22, 1473–1482 (2017). https://doi.org/10.1038/mp.2016.261
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