Tottering Mice Research Articles

Down regulation of sodium channels in nerve terminals of spontaneously epileptic mice.

Tottering mice, in which a single gene lesion leads to prolonged hyperexcitability and spontaneous epilepsy, were studied to determine whether enhanced electrical activity leads to down regulation of sodium channels in central neurons. The number of sodium channels in synaptosomes, as assessed by saxitoxin binding, was decreased from 5.38 +/- 0.06 pmol/mg protein in coisogenic controls to 3.85 +/- 0.10 pmol/mg protein (P less than 0.001) in tottering mice without a change in the KD for saxitoxin. Neurotoxin-activated 22Na+ influx per sodium channel was increased 80% in tottering mice (P less than 0.001). Evidently, the increased level of electrical excitability characteristic of the tottering phenotype causes down regulation of the sodium-channel number and alteration of channel function in the nerve terminals of central neurons.

Decreased Muscarinic Acetylcholine Receptor Number in the Central Nervous System of the Tottering (tg/tg) Mouse

The tottering mouse (tg/tg) is a single-locus mutant, phenotypically characterized by the development of epilepsy associated with distinct electroencephalographic abnormalities. Because of reported alterations in muscarinic receptor (mAChR) number in various seizure states, mAChR density was examined in discrete brain regions of tottering (tg/tg) and coisogenic wild-type (+/+) mice. Saturation binding experiments revealed a widespread decrease in membrane mAChR density in the CNS of adult tottering (tg/tg) mice as compared with age-matched control wild-type (+/+) mice. The decrease was most pronounced in the hippocampus, where tg/tg mice exhibited a 40-60% reduction in mAChR density with no change in the affinity of the receptor for antagonists or agonists. At postnatal day 10, before the reported onset of electroencephalographic abnormalities, 114 and 65% increases in mAChR density were observed in the tg/tg hippocampus and cortex, respectively. Following the development of seizure activity at postnatal day 22, mAChR density in the tg/tg hippocampus was reduced by 29%. No change in brain mAChR density was seen in adult heterozygotes (+/tg), which do not develop electroencephalographic or seizure abnormalities. These results indicate that the development of reduced mAChR number in the CNS of the tg/tg mouse is secondary to abnormal neuronal activity, providing further support for the hypothesis that membrane depolarization can cause a decrease in neuronal mAChR density.

Anticonvulsant sensitivity of absence seizures in the tottering mutant mouse.

Homozygous tottering mice (tg, autosomal recessive) exhibit frequent spontaneous "absence" seizures accompanied by bilaterally synchronous spike-and-wave or polyspike electrocorticographic discharges. In adult tottering mice, the antiepileptic effects of a single dose of ethosuximide, diazepam, phenobarbital, or phenytoin were assessed using continuous electrocorticographic recording to monitor seizure incidence. The dose chosen for each drug was selected to correspond to an effective antiepileptic dose in standard murine models. Ethosuximide, 150 mg/kg, diazepam, 1.4 mg/kg, and phenobarbital, 25 mg/kg were effective against absence seizures. In contrast, phenytoin at 5, 10, 30, or 60 mg/kg produced no significant reduction in the incidence of absence seizures. These results suggest that absence seizures in the tottering mutant may represent a relatively specific pharmacological model for the identification of drugs effective for clinical absence epilepsy, and emphasize the potential value of this new model for the study of fundamental mechanisms of absence of epilepsy and the actions of antiepileptic drugs.

Effects of the tottering mutation in the mouse: Multiple neurologic changes

The homozygote mutant mouse tottering (chromosomal designation tg) is distinguished from the heterozygote by an ataxic gait and the occurrence of spontaneous stereotypic seizures. We determined the effects of this mutation on other neurally controlled behaviors. Three behaviors were studied: swimming ability, balance on the rotorod, and activity in the open field. Swimming ability was greatly reduced ( P < 0.001) in ( tg tg ) mice compared with wild type C57BL 6J (+/+) mice when rated on a scale designed to measure “swimming success,” whereas scores for “vigor” were normal. Heterozygotes ( tg/+) had normal swimming “vigor” but showed a bimodal distribution on the “success” scale. Open field activity of ( tg tg ) mice was significantly less ( P < 0.002) compared with heterozygote littermates. Homogyzous tottering mice were unable to maintain balance on a rotating wooden rod (rotorod test), whereas heterozygotes readily learned this task. Brain weights of 8-week-old mice were examined and found to be equal except for the cerebellum, which weighed less in ( tg tg ) mice. No significant differences in the degree of impairment between sexes or the age of testing were found. These results suggest a widespread involvement of the tg gene mutation in normal mouse behavior; however, other interpretations have not been ruled out.

Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation.

The central catecholamine neuron system in the mutant mouse tottering was examined by fluorescence histochemistry and biochemical analysis of catecholamine content. This single-locus neurological mutation expresses a reproducible alteration in central nervous system physiology characterized by spontaneous spike-wave and focal motor seizures in the absence of any previously recognized disturbance of cellular organization or brain size. Histochemical analysis showed a significant increase in the number of noradrenergic axons in terminal fields innervated by the nucleus locus ceruleus when compared with the wild type. A concomitant 100-200% rise in norepinephrine levels is found in the same areas, including hippocampus, cerebellum, and dorsal lateral geniculate. Catecholamine fibers and transmitter content in areas innervated by a second major noradrenergic system arising from the brainstem lateral tegmental neurons are unaltered. The terminal axons and transmitter content were both unchanged in nuclei receiving a dense dopaminergic innervation. Despite the hypertrophy of the locus ceruleus axonal plexus, the number and size of locus ceruleus cell somata were identical in both wild-type and tottering mice. These findings are consistent with a specific gene-linked alteration of developmental events controlling the number of axons produced by a single neuronal population in the mammalian brain.

Spontaneous polyspike discharges in an epileptic mutant mouse (tottering)

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.

Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering.

Mice with the mutant gene tottering (tg, chromosome 8, autosomal recessive) show, in adolescence, abnormal bursts of bilaterally synchronous spike waves as revealed in electrocorticograms recorded over long periods. The spike waves are accompanied by behavioral "absence" attacks and intermittent focal motor seizures showing somatotopic progression. Cerebral metabolic activity during seizures was assayed by autoradiography of brain sections from mice injected intravenously with 14C-labeled 2-deoxyglucose. Metabolic activity was increased bilaterally in selected brainstem structures. Spontaneous electrocorticographic and clinical seizures of this general pattern were recognized hitherto only in humans.