Phospholipase C beta 4 in the medial septum controls cholinergic theta oscillations and anxiety behaviors.
Anxiety is among the most prevalent and costly diseases of the CNS, but its underlying mechanisms are not fully understood. Although attenuated theta rhythms have been observed in human subjects with increased anxiety, no study has been done on the possible physiological link between these two manifestations. We found that the mutant mouse for phospholipase C beta 4 (PLC-beta 4(-/-)) showed attenuated theta rhythm and increased anxiety, presenting the first animal model for the human condition. PLC-beta 4 is abundantly expressed in the medial septum, a region implicated in anxiety behavior. RNA interference-mediated PLC-beta 4 knockdown in the medial septum produced a phenotype similar to that of PLC-beta 4(-/-) mice. Furthermore, increasing cholinergic signaling by administering an acetylcholinesterase inhibitor cured the anomalies in both cholinergic theta rhythm and anxiety behavior observed in PLC-beta 4(-/-) mice. These findings suggest that (1) PLC-beta 4 in the medial septum is involved in controlling cholinergic theta oscillation and (2) cholinergic theta rhythm plays a critical role in suppressing anxiety. We propose that defining the cholinergic theta rhythm profile may provide guidance in subtyping anxiety disorders in humans for more effective diagnosis and treatments.
Shin
Jonghan
J
Neuroscience Research Institute, Gachon University of Medicine and Science, Incheon 405-760, Republic of Korea, Center for Neural Science, Korea.
Gireesh
Gangadharan
G
Kim
Seong-Wook
SW
Kim
Duk-Soo
DS
Lee
Sukyung
S
Kim
Yeon-Soo
YS
Watanabe
Masahiko
M
Shin
Hee-Sup
HS
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004569:Electroencephalography; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D007150:Immunohistochemistry; D055029:Inverted Repeat Sequences; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D048448:Phenylcarbamates / Q000494:pharmacology; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000068836:Rivastigmine; D020665:Septum of Brain / Q000187:drug effects / Q000503:physiopathology*; D013826:Theta Rhythm
D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D054799:Phospholipase C beta; C518043:Plcb4 protein, mouse; D000109:Acetylcholine; D000068836:Rivastigmine