title: Kv4 channel blockade reduces motor and neuropsychiatric symptoms in rodent models of Parkinson's disease.
abstract: The striatum, a major input structure of basal ganglia, integrates glutamatergic cortical and thalamic inputs to control psychomotor behaviors. Nigrostriatal dopamine (DA) neurodegeneration in Parkinson's disease causes a loss of spinal and glutamatergic synapses in the striatal medium spiny neurons (MSNs). Adaptive responses, a form of homeostatic plasticity, to these changes are caused by a decrease in a potassium Kv4 channel-dependent inactivating A-type potassium (KIA) current that increases the intrinsic excitability of MSNs. Nevertheless, the functional outcome of these compensatory mechanisms does not allow adequate behavioral recovery in vivo. We thus addressed the question of whether further blockade of Kv4 activity could enhance the striatal responsiveness of MSNs to DA depletion and restore normal function in vivo. To test this hypothesis, we examined the effects of a selective blocker of Kv4 channels, AmmTX3, on the motor, cognitive, and emotional symptoms produced by 6-hydroxydopamine lesions of the nigrostriatal DA pathway in rats. Striatal infusion of AmmTX3 (0.2-0.4 μg) reduced motor deficits, decreased anxiety, and restored short-term social and spatial memories. These results underlie the importance of Kv4 channels as players in the homeostatic responses, and, more importantly, provide a potential target for adjunctive therapies for Parkinson's disease.
authors.affiliation: aCNRS - Aix-Marseille University, Cognitive Neuroscience Laboratory, UMR7291,Marseille, France bUnit of Functional Proteomics and Organic Food Preservation, Higher Institute of Applied Biological Sciences of Tunis, University of Tunis El Manar, Tunis cHigher Institute of Environmental Sciences and Technologies, University of Carthage, Carthage, Tunisia.
authors.forename: Sabrine
authors.initials: S
authors.lastname: Aidi-Knani
authors.forename: Imed
authors.initials: I
authors.lastname: Regaya
authors.forename: Marianne
authors.initials: M
authors.lastname: Amalric
authors.forename: Christiane
authors.initials: C
authors.lastname: Mourre
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012604:Scorpion Venoms / Q000008:administration & dosage / Q000494:pharmacology*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C471416:AmmTX3 protein, Androctonus mauretanicus; D000978:Antiparkinson Agents; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D051672:Shal Potassium Channels; D016627:Oxidopamine; D004298:Dopamine