title: mGlu1 receptor mediates homeostatic control of intrinsic excitability through Ih in cerebellar Purkinje cells.
abstract: Homeostatic intrinsic plasticity is a cellular mechanism for maintaining a stable neuronal activity level in response to developmental or activity-dependent changes. Type 1 metabotropic glutamate receptor (mGlu1 receptor) has been widely known to monitor neuronal activity, which plays a role as a modulator of intrinsic and synaptic plasticity of neurons. Whether mGlu1 receptor contributes to the compensatory adjustment of Purkinje cells (PCs), the sole output of the cerebellar cortex, in response to chronic changes in excitability remains unclear. Here, we demonstrate that the mGlu1 receptor is involved in homeostatic intrinsic plasticity through the upregulation of the hyperpolarization-activated current (Ih) in cerebellar PCs. This plasticity was prevented by inhibiting the mGlu1 receptor with Bay 36-7620, an mGlu1 receptor inverse agonist, but not with CPCCOEt, a neutral antagonist. Chronic inactivation with tetrodotoxin (TTX) increased the components of Ih in the PCs, and ZD 7288, a hyperpolarization-activated cyclic nucleotide-gated channel selective inhibitor, fully restored reduction of firing rates in the deprived neurons. The homeostatic elevation of Ih was also prevented by BAY 36-7620, but not CPCCOEt. Furthermore, KT 5720, a blocker of protein kinase A (PKA), prevented the effect of TTX reducing the evoked firing rates, indicating the reduction in excitability of PCs due to PKA activation. Our study shows that both the mGlu1 receptor and the PKA pathway are involved in the homeostatic intrinsic plasticity of PCs after chronic blockade of the network activity, which provides a novel understanding on how cerebellar PCs can preserve the homeostatic state under activity-deprived conditions.
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea;
authors.forename: Hyun Geun
authors.initials: HG
authors.lastname: Shim
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea; Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea;
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Jang
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Brain and Cognitive Sciences, College of Science, Seoul National University, Kwanak-gu, Seoul, Republic of Korea;
authors.forename: Dong Cheol
authors.initials: DC
authors.lastname: Jang
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea; and.
authors.forename: Yunju
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Chang
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea; and.
authors.forename: Joo Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Republic of Korea; Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; sangjkim@snu.ac.kr.
authors.forename: Sang Jeong
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000200:Action Potentials; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006706:Homeostasis; D009281:Naphthalenes / Q000494:pharmacology; D009473:Neuronal Plasticity; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; C425484:BAY36-7620; D002227:Carbazoles; D002867:Chromones; D009281:Naphthalenes; D011758:Pyrroles; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D013779:Tetrodotoxin; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Ih; homeostatic plasticity; intrinsic excitability; mGlu1 receptor