Spontaneous polyspike discharges in an epileptic mutant mouse (tottering)

doi:10.1016/0014-4886(79)90203-6

Experimental Neurology

Volume 66, Issue 3, December 1979, Pages 577-586

https://doi.org/10.1016/0014-4886(79)90203-6 Get rights and content

Abstract

Electroencephalographic (EEG) recordings were made from unanesthetized, freely moving tottering mice. This neurological mutant exhibits spontaneous motor seizures. Although the intention of the present study was to determine an electrographic correlate of the motor seizures, no epileptiform discharge was found which was reliably associated with this type of ictal event. The present study revealed the occurrence of a paroxysmal pattern which appeared independently of the motor seizures. The polyspike pattern was a $6 s$ burst resembling the $3 s$ spike-wave complex often recorded in human epileptics. The waking behavior associated with the polyspiking in the tottering mice consisted of immobility and staring. In addition, polyspike bursts occurred during drowsiness. It is possible that the cerebellar defects found in tottering mice are related to their gait disturbance and to their motor seizures. The polyspike discharge appears to represent an independent ictal event, suggesting that tottering mice are susceptible to both motor and “absence” seizures. Previously documented examples of naturally occurring epilepsy consisted primarily of stimulus-evoked or “reflex” seizures. Tottering mice show promise for research of spontaneous, recurrent paroxysmal activity in a hereditary type of epilepsy.

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Episodic ataxia type 2 (EA2) is a disorder characterized by acute attacks of ataxia precipitated by stress, ethanol, and caffeine. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α₁ pore-forming subunit of the Ca_v2.1 (P/Q-type) voltage-gated calcium channel. Several mouse strains, including tottering mice, carry loss-of-function mutations in the Cacna1a gene and have been used to investigate the pathomechanisms of EA2. Like EA2 patients, tottering mice exhibit attacks of motor dysfunction triggered by stress, ethanol, and caffeine. The cerebellum and specifically cerebellar Purkinje cells are implicated in tottering mouse attacks. Like EA2 patients, drugs that restore Purkinje cell pacemaking, such as 4-aminopyradine, block tottering attacks. Other mouse strains, such as rocker, leaner, and engineered strains, display a range of phenotypes, from mild, paroxysmal motor dysfunction to chronic dystonia, similar to the range of neurological problems exhibited by EA2 patients. Cacna1a mutant mice have provided insights into the neurobiology of EA2 and into the mechanisms underlying treatments and may, therefore, prove useful for developing novel and more efficacious therapeutics.
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The dystonic motor behavior itself arises from maladaptive molecular plasticity involving secondary up-regulation of CaV1.2 [L-type] calcium channels (Campbell and Hess, 1998, 1999; Daniel et al., 1999), as blocking these channels suppresses the induction of dystonic attacks (Campbell and Hess, 1999; Fureman et al., 2002). Defects in this gene lead to paroxysmal or focal dystonia in humans (Kaplan et al., 1979; Spacey et al., 2005). The attacks are correlated with the accentuation of low frequency oscillations in cerebellar cortex (Chen et al., 2009).
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Thus, tottering mice can be diagnosed with paroxysmal dyskinesis, a type of movement disorder. Mice do not lose consciousness during an attack and thus are not a suitable model for complex seizures, although the slow-wave electroencephalographic discharges qualify tottering mice as a model for absence epilepsy as evidenced by brief periods of inactivity together with 6-Hz polyspike discharges [154,155]. Infrequent seizures may arise spontaneously or, alternatively, be triggered by exposure to caffeine, ethanol, or a variety of novel environments [156].
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Episodic neurological dysfunction often results from ion channel gene mutations. Despite knowledge of the mutations, the factors that precipitate attacks in channelopathies are not clear. In humans, mutations of the calcium channel gene CACNA1A are associated with attacks of neurological dysfunction in familial hemiplegic migraine and episodic ataxia type-2. In tottering mice, a mutation in the same gene causes attacks resembling paroxysmal dyskinesia. Stress, a trigger associated with human episodic disorders, reliably elicits attacks in tottering mice. Because noradrenergic neurotransmission is critical to the stress response and because noradrenergic hyperinnervation is observed in tottering mice, the role of norepinephrine in stress-induced attacks was investigated. Drugs that act at α-adrenergic receptors to block noradrenergic transmission prevented attacks. However, agents that facilitate noradrenergic neurotransmission failed to induce attacks. These results suggest that, while noradrenergic neurotransmission may be necessary for attacks, an increase in norepinephrine is not sufficient to induce attacks.

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²: Dr. Kaplan's present address is Alberta Children's Hospital, 1820 Richmond Rd., Calgary, Alberta T2T 5C7, Canada.

¹: This investigation was supported by the Esther A. and Joseph Klingenstein Fund, the Swebilius Fund, and U.S. Public Health Service Postdoctoral Fellowship 1F32NS05443 (T.N.S.).

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Spontaneous polyspike discharges in an epileptic mutant mouse (tottering)

Abstract

Electroenceph. Clin. Neurophysiol.

Physiol. Behav.

Electroenceph. Clin. Neurophysiol.

Electroenceph. Clin. Neurophysiol.

Physiol. Behav.

Epileptiform seizures in domestic fowl

J. Hered.