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Forebrain-specific ablation of phospholipase C gamma 1 causes manic-like behavior

Title
Forebrain-specific ablation of phospholipase C gamma 1 causes manic-like behavior
Authors
Yang, Y. R.Jung, J. H.Kim, S-JHamada, K.Suzuki, A.Kim, H. J.Lee, J. H.Kwon, O-BLee, Y. K.Kim, J.Kim, E-KJang, H-JKang, D-SChoi, J-SLee, C. J.Marshall, J.Koh, H-YKim, C-JSeok, H.Kim, S. H.Choi, J. H.Choi, Y-BCocco, L.RYU, SUNG HOKim, J-HSuh, P-G
POSTECH Authors
RYU, SUNG HOKim, J-H
Date Issued
Oct-2017
Publisher
NATURE PUBLISHING GROUP
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 C gamma 1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase C gamma 1 (PLC gamma 1) in the forebrain (Plcg1(f/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 gamma-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 Plcg1(f/f); CaMKII mice. These findings provide evidence that PLC gamma 1 is critical for synaptic function and plasticity and that the loss of PLC gamma 1 from the forebrain results in manic-like behavior.
Keywords
LONG-TERM POTENTIATION; BIPOLAR DISORDER; SIGNALING PATHWAYS; GABA(A) RECEPTORS; NERVOUS-SYSTEM; TRKB; GENE; BDNF; HIPPOCAMPUS; KINASE
URI
http://oasis.postech.ac.kr/handle/2014.oak/50776
DOI
10.1038/mp.2016.261
ISSN
1359-4184
Article Type
Article
Citation
MOLECULAR PSYCHIATRY, vol. 22, no. 10, page. 1473 - 1482, 2017-10
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 RYU, SUNG HO
Dept of Life Sciences
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