title: Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism.
abstract: The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels.
authors: IFIBIO Bernardo Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires - CONICET, 2155 Paraguay Street, Buenos Aires 1121, Argentina. Electronic address: cecitubert@gmail.com.
authors: Cecilia
authors: C
authors: Tubert
authors: Neurobiología Experimental, Universidad de Entre Ríos, Gualeguaychú, Entre Ríos E2822EXB, Argentina.
authors: Irene R E
authors: IRE
authors: Taravini
authors: Department of Cellular and Molecular Pharmacology, The Chicago Medical School at Rosalind Franklin University, Chicago, IL 60064, USA.
authors: Eden
authors: E
authors: Flores-Barrera
authors: IFIBIO Bernardo Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires - CONICET, 2155 Paraguay Street, Buenos Aires 1121, Argentina.
authors: Gonzalo M
authors: GM
authors: Sánchez
authors: IFIBIO Bernardo Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires - CONICET, 2155 Paraguay Street, Buenos Aires 1121, Argentina.
authors: María Alejandra
authors: MA
authors: Prost
authors: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), CONICET, Buenos Aires 1428, Argentina.
authors: María Elena
authors: ME
authors: Avale
authors: Department of Cellular and Molecular Pharmacology, The Chicago Medical School at Rosalind Franklin University, Chicago, IL 60064, USA.
authors: Kuei Y
authors: KY
authors: Tseng
authors: IFIBIO Bernardo Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires - CONICET, 2155 Paraguay Street, Buenos Aires 1121, Argentina.
authors: Lorena
authors: L
authors: Rela
authors: IFIBIO Bernardo Houssay, Grupo de Neurociencia de Sistemas, Facultad de Medicina, Universidad de Buenos Aires - CONICET, 2155 Paraguay Street, Buenos Aires 1121, Argentina.
authors: Mario Gustavo
authors: MG
authors: Murer
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D018678:Cholinergic Agents / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D017072:Neostriatum / Q000378:metabolism*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology*; D010641:Phenotype; D021122:Protein Subunits / Q000378:metabolism; D012604:Scorpion Venoms / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018678:Cholinergic Agents; D051664:Kv1.3 Potassium Channel; D021122:Protein Subunits; D012604:Scorpion Venoms; C077910:margatoxin; D016627:Oxidopamine