title: Involvement of kv1 potassium channels in spreading acidification and depression in the cerebellar cortex.
abstract: Spreading acidification and depression (SAD) is a form of propagated activity in the cerebellar cortex characterized by acidification and a transient depression in excitability. This study investigated the role of Kv1 potassium channels in SAD using neutral red, flavoprotein autofluorescence, and voltage-sensitive dye optical imaging in the mouse cerebellar cortex, in vivo. The probability of evoking SAD was greatly increased by blocking Kv1.1 as well as Kv1.2 potassium channels by their specific blockers dendrotoxin K (DTX-K) and tityustoxin (TsTX), respectively. DTX-K not only greatly lowered the threshold for evoking SAD but also resulted in multiple cycles of spread and spontaneous SAD. The occurrence of spontaneous SAD originating from spontaneous parallel fiber-like beams of activity suggests that blocking Kv1 channels increased parallel fiber excitability. This was confirmed by the generation of parallel fiber-like beams with the microinjection of glutamate into the upper molecular layer in the presence of DTX-K. The dramatic effects of DTX-K suggest a possible connection between SAD and episodic ataxia type 1 (EA1), a Kv1.1 potassium channelopathy. The threshold for evoking SAD was significantly lowered in the Kv1.1 heterozygous knockout mouse compared with wild-type littermates. Carbamazepine and acetazolamide, both effective in the treatment of EA1, significantly decreased the likelihood of evoking SAD. Blocking GABAergic neurotransmission did not alter the effectiveness of DTX-K. The cyclin D2 null mouse, which lacks cerebellar stellate cells, also exhibited SAD. Therefore blocking Kv1 potassium channels establishes the conditions needed to generate SAD. Furthermore, the results are consistent with the hypothesis that SAD may underlie the transient attacks of ataxia characterizing EA1.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Wangcai
authors.initials: W
authors.lastname: Gao
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Reinert
authors.forename: Laurentiu S
authors.initials: LS
authors.lastname: Popa
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Hendrix
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Ross
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ebner
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000143:Acids / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000502:physiology*; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D003952:Diagnostic Imaging / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009499:Neutral Red / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000172:deficiency / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects; D012604:Scorpion Venoms / Q000494:pharmacology; D051637:Shaker Superfamily of Potassium Channels; D013997:Time Factors
chemical_list: D000143:Acids; D000927:Anticonvulsants; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D018756:GABA Antagonists; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012604:Scorpion Venoms; D051637:Shaker Superfamily of Potassium Channels; C081506:dendrotoxin K; D009499:Neutral Red; D002220:Carbamazepine; C003609:tityustoxin; D018698:Glutamic Acid; D001418:Baclofen; C080629:saclofen; D000086:Acetazolamide; D001640:Bicuculline