title: Abnormal excitability and episodic low-frequency oscillations in the cerebral cortex of the tottering mouse.
abstract: The Ca(2+) channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Cav2.1 (P/Q-type) voltage-gated Ca(2+) channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex of tottering (tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs in tg/tg mice can spontaneously develop very high power, referred to as a high-power state. The LFOs in tg/tg mice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca(2+) channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking l-type Ca(2+) channels, known to be upregulated in tg/tg mice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs in tg/tg but not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in the tg/tg cerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterize CACNA1A mutations.
authors: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
authors: Samuel W
authors: http://orcid.org/0000-0002-7103-4182
authors: SW
authors: Cramer
authors: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
authors: Laurentiu S
authors: LS
authors: Popa
authors: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
authors: Russell E
authors: RE
authors: Carter
authors: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455.
authors: Gang
authors: G
authors: Chen
authors: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455 ebner001@umn.edu.
authors: Timothy J
authors: TJ
authors: Ebner
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D053447:Channelopathies / Q000235:genetics* / Q000473:pathology*; D003344:Cortical Synchronization / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines; D011810:Quinoxalines / Q000494:pharmacology; D014738:Vibrissae / Q000294:innervation
chemical_list: D015761:4-Aminopyridine; D000086:Acetazolamide; D044482:Benzeneacetamides; D020864:Calcium Channels, N-Type; D004791:Enzyme Inhibitors; D019331:NG-Nitroarginine Methyl Ester; D018377:Neurotransmitter Agents; D052250:Nitric Oxide Synthase Type III; D026902:Potassium Channel Blockers; D011725:Pyridines; D011810:Quinoxalines; C579131:2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide; C056723:FG 9041
keywords: calcium channelopathy; cerebral cortex; episodic ataxia type 2; episodic nervous system dysfunction; flavoprotein optical imaging; tottering mouse