Abnormal excitability and episodic low-frequency oscillations in the cerebral cortex of the tottering mouse

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The Ca 2+ channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Ca v2.1 (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.

Original languageEnglish (US)
Pages (from-to)5664-5679
Number of pages16
JournalJournal of Neuroscience
Issue number14
StatePublished - Apr 8 2015

Bibliographical note

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  • Calcium channelopathy
  • Cerebral cortex
  • Episodic ataxia type 2
  • Episodic nervous system dysfunction
  • Flavoprotein optical imaging
  • Tottering mouse


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