Abnormal Excitability and Episodic Low-Frequency Oscillations in the Cerebral Cortex of thetotteringMouse

Abstract

The Ca 2ϩ channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Ca v 2.1 (P/Q-type) voltage-gated Ca 2ϩ 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 2ϩ channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking L-type Ca 2ϩ 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.

Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy

“…Following the initial increase in flavoprotein autofluorescence, there was a prolonged decrease in autofluorescence (Fig. 1B), similar to that previously reported for the cerebellar and cerebral cortex (Shibuki et al 2003;Reinert et al 2004;Brennan et al 2006;Cramer et al 2015). The response amplitude was 2.38 ± 0.87% in the ipsilateral hemisphere, but was significantly smaller in the contralateral side at 1.48 ± 0.58% (Fig.…”

“…The mesoscopic capabilities of flavoprotein imaging (Cramer et al 2015;Ma et al 2016;Kozberg et al 2016) allowed us to image large regions of the exposed cerebral cortex including the intra- and intercortical responses to intracortical stimulation. Train stimulation of the motor cortex resulted in both an ipsilateral and contralateral increase in flavoprotein fluorescence and the latter was mediated by neuronal activation through the corpus callosum.…”

“…1). The train stimulation evoked an initial increase in fluorescence followed by a decrease in fluorescence (Shibuki et al 2003;Reinert et al 2004;Coutinho et al 2004;Cramer et al 2015). The former results from the oxidation of mitochondrial flavoproteins in postsynaptic neurons and is tightly coupled to stimulation strength (Shibuki et al 2003;Reinert et al 2004;Brennan et al 2006;Reinert et al 2007).…”

“…The flavoprotein signal reflects the underlying neuronal responses as assessed by field potentials or single unit activity and is therefore, a highly useful mapping signal (Shibuki et al 2003;Coutinho et al 2004;Husson et al 2007;Wang et al 2011;Cramer et al 2013). Flavoprotein imaging, like intrinsic optical imaging (Lieke et al 1989), allows for a wide field-of-view of neuronal activity across a large area of the brain (Cramer et al 2015;Ma et al 2016;Kozberg et al 2016). Therefore, this type of mesoscopic imaging provides an important tool to evaluate normal and abnormal response patterns and complements the cellular resolution, but more limited field-of-view, of two-photon imaging.…”

Personalized medicine in epilepsy patients

“…De novo missense mutations have been convincingly shown to cause severe epileptic encephalopathies with seizure types that typically include focal, tonic, and tonic-clonic seizures, severe intellectual disability and motor impairment [127,128] . It is known that acetazolamide and 4-aminopyridine are able to decrease, in tottering mice, the high-power low-frequency oscillations, which are thought to be a marker of cortical excitability, so these drugs are evaluated as treatment options for episodic ataxia 2 [129] . Spontaneous seizures in the CACNA1A knockout mouse can be abolished by knocking out CACNA1G [130] .…”