Selection for spontaneous or priming-induced audiogenic seizure susceptibility in mice

Four lines of mice were selectively bred from a heterogeneous foundation stock for audiogenic seizure prone (SP), priming prone (PP), moderately priming prone (MPP), and seizure resistant (SR). Significant changes in proportions of animals showing the desired phenotypes were found after two generations of selection, indicating involvement of genetic components in these behavioral characteristics. Although response to selection for spontaneous seizure proneness was rapid, the results do not support a view that initial seizure risk is controlled by a single recessive gene. The effects of tympanic membrane perforation on development of seizure susceptibility in these four selected lines were investigated in Experiment 2. Results indicate that the method is highly effective in inducing seizure susceptibility in the PP mice and the SR mice, but not so effective for the SP and the MPP lines. These results suggest that spontaneous and priming-induced seizure susceptibility could be due to development of hyperreactivity in centripetal auditory structures brought about by reduction of auditory input. They also suggest that the phenotypic difference between the PP and the SR lines could be due to differences in their cochlear susceptibility to stimulation damage but that a qualitatively different mechanism is involved in the MPP line.     

Genomic imprinting and audiogenic seizures in mice

Audiogenic seizure (AGS) susceptibility in mice is a multifactorial behavioral disorder that involves severe generalized convulsions in response to loud, high-frequency sound. The inheritance of AGS susceptibility was examined in crosses between AGS-susceptible DBA/2J (D2) mice and epilepsy-prone (EP) mice. The EP mice were selected for high AGS susceptibility in a BALB/c-derived line. The AGS phenotype was similar in the EP and D2 mice at 30 days of age. The frequency of generalized clonic-tonic AGS was high in both the D2 and the EP mice (53 and 83%, respectively) but was low in the reciprocal EPD2F1 and D2EPF1 hybrids (14 and 19%, respectively). In the backcross to the EP parent, no significant associations were found between AGS susceptibility and microsatellite markers linked to Asp1 or Asp2, AGS genes located on Chromosomes 12 and 4, respectively. Significant associations were found for markers linked to Asp3, which is located in the proximal region of Chromosome 7. The influence of Asp3 on AGS susceptibility was seen in the EP x EPD2F1 backcross but not in the reciprocal EPD2F1 x EP backcross, suggesting that Asp3 expression is influenced by genomic imprinting. A model is proposed where genomic imprinting represses the maternal Asp3 allele, providing an influence largely from the paternal allele.     

Electroencephalographic correlates of audiogenic seizures during ethanol withdrawal in mice

C57BL/6Bg mice had silver bead electrodes chronically implanted on the surface of the cortex and had their cortical EEG recorded during audiogenic seizures following ethanol withdrawal. For 7 days, the experimental groups were fed a liquid diet containing 6% v/v ethanol ad lib as the only source of food and water. The control group was fed a similar diet containing an isocaloric amount of sucrose. The cortical EEG's of experimental and control groups before, during, and after treatment were virtually identical. Only the experimental group was susceptible to audiogenic seizures. During audiogenic seizures, the cortical EEG showed no sign of spike waves or paroxysmal activity. This is in contrast to picrotoxin convulsions with these same mice as well as to spontaneous convulsions in animals following ethanol withdrawal. Similar EEG observations have been reported on audiogenic seizures from genetic and acoustically primed susceptibilities. Consequently, we suggest that all audiogenic seizure responses, including those during ethanol withdrawal, are a type of subcortical epilepsy.     

Effects of priming for audiogenic seizures in mice as a function of genotype and sound intensity.

Studied the effects of sound-intensity levels and genotypes on priming for audiogenic seizures in 367 mice of the BALB/c, C57BL/J Rubbo, and C57BL/K Bradley strains and their F1 hybrids. Significant main effects for Strain, Sound Intensity, and Genotype * Treatment interaction, and a variability of mode of inheritance, depending upon particular genotypes and treatments, were observed. A 96-db sound was not effective in inducing seizure susceptibility in all genotypes; a 101-db sound induced moderate seizure rate in BALB/c and K Bradley Ss but not in the other strains; a 104-db sound induced a high seizure rate in BALB/c, but a moderate rate in K Bradley and BALB/c * J Rubbo Ss; at 109-db level, a high seizure rate was induced in BALB/c and BALB/c * J Rubbo Ss and a moderate rate in K Bradley. (23 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interference with priming for audiogenic seizures in BALB/c mice by prior auditory stimulation.

Conducted 3 experiments with BALB/c inbred mice (N = 111) to test a simple method for reducing the effect of priming for audiogenic seizures which is known to be resistant to many variables. Exp. I showed that the priming effect could substantially be reduced by exposing ether-anesthetized Ss, prior to priming, to an intense sound that was previously found to be effective in inducing audiogenic seizures. Exp. II showed that ether anesthesia was not the primary factor for this protective effect, suggesting that it may just potentiate the effect of prepriming auditory stimulation. Exp. III, in addition to replicating most of the results of Exp. I and II, showed that this protective effect could be reversed, paradoxically, by ether anesthesia during priming. (15 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Roles of anoxia and noise-induced hearing loss in the postictal refractory period for audiogenic seizures in mice.

Three experiments with 188 Ss demonstrated a postictal refractory period for audiogenic seizures in DBA/2J mice, which was not related to hearing loss but apparently was related to anoxia. Exp I controlled for the effects of noise exposure upon hearing sensitivity and demonstrated reduced susceptibility to subsequent audiogenic seizures for at least 1 hr after initial clonic-tonic convulsions. The postictal refractory period resulted from the occurrence of seizures per se, not from noise exposure alone. Exp II demonstrated deficiencies of sensorimotor functions that accompanied reduced postictal seizure susceptibility. The 2 phenomena had similar time courses of recovery, which suggested a common mechanism, probably anoxia, associated with the initial convulsions. In support of this view, Exp III shows that recovery from both phenomena was expedited by allowing Ss to breathe increased O-sub-2. The role of anoxia in fatal convulsions is suggested by the finding that Ss experiencing clonic-tonic convulsions in a high-O-sub-2 environment survived without exception. In contrast, seizures of air-breathing controls were almost always fatal. The data indicate that the postictal reduced susceptibility to audiogenic seizures was closely related to metabolic depletion (in particular, anoxia). The pattern of recovery of susceptibility further suggests that the effects of anoxia impair the spread of seizure activity through the CNS, although the initiation of seizures is also affected for a short time. (44 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pinna reflex thresholds and audiogenic seizures: Developmental changes after acoustic priming.

Exposed 200 16-day-old C57BL/6J mice to 30 sec. of 120-db noise (acoustic priming). Primed Ss and 220 unprimed Ss were tested on subsequent days for either audiogenic seizures or an altered threshold to the Preyer pinnal reflex. Within 24 hr., the Preyer reflex threshold had decreased in primed Ss by 5.4 db., and a further decline of 10.1 db. occurred over the next 4 days. The 2 indices of audiogenic seizures did not show a corresponding change until the 2nd day after priming. It is hypothesized that acoustic priming selectively disrupts inhibitory mechanisms which normally protect the CNS from an overload by intense sounds, and that audiogenic seizures and the Preyer reflex are independently affected by this common event. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reduced exploratory activity of audiogenic seizures susceptible Wistar rats

To search for the existence of a tumour-suppressor gene (TSG) associated with oral squamous cell carcinoma (SCC), PCR analysis of microsatellite polymorphisms corresponding to 14 loci which map to chromosome 7q21.3-qter was performed to screen 35 patients with oral SCC for loss of heterozygosity (LOH). LOH was observed in at least one of the loci in 19 of 34 (55.9%) informative cases. Among the loci tested, frequent LOH was restricted at D7S522 on chromosome 7q31.1, which was measured within 1 cM. Furthermore, we detected microsatellite instability (MI) in 11 of 35 (31.4%) cases tested. Our observations indicate that alterations of chromosome 7q are associated with oral SCC tumorigenesis and that 7q31.1 might harbour at least one putative TSG.     

Changes in cochlear microphonic sensitivity after priming C57BL/6J mice at various ages for audiogenic seizures.

Approximately 150 C57BL/6J mice were briefly exposed to a 1-octave band of noise at 14, 18, 28, 38, or 58 days of age. Five days later the groups were divided, and some mice were behaviorally tested for audiogenic seizures by reexposing them to the same sound. The round window cochlear microphonic potential was measured in the remaining Ss and compared with that observed in unprimed control Ss. Seizure behavior occurred in all Ss primed on Day 18 but rarely for Ss in the other age groups. Cochlear microphonic threshold curves in mice primed on Day 18 showed a 30-db loss in sensitivity, while all other primed groups showed little change. Data are discussed in terms of the "disuse-supersensitivity" hypothesis previously proposed to account for the physiological effects of priming in mice. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic linkage between the AH locus and a major gene that inhibits susceptibility to audiogenic seizures in mice

Mice of the DBA/2 (D2) strain are highly susceptible to sound-induced seizures at 21 days of age; whereas, mice of the C57BL/6 (B6) strain are resistant to these seizures. Although the difference in susceptibility to audiogenic seizures (ASs) between these two strains is inherited as a multiple-factor trait, an association was observed between susceptibility to ASs and the Ah locus. The Ah locus controls the inducibility of aryl hydrocarbon hydroxylase (AHH) activity by a number of aromatic hydrocarbons. B6 mice carry the Ahb allele and have inducible AHH activity; whereas, D2 mice carry the Ahd allele and have noninducible activity. Inducibility is inherited as a Mendelian dominant trait in crosses between these strains. Mice carrying the Ahb allele are generally less susceptible to ASs sat 21 days of age than are mice carrying the Ahd allele. The combined results from B6 X D2 recombinant inbred strains, congenic strains (where the Ahb allele was placed into the D2 genome and the Ahd allele placed into the B6 genome), the B6D2F1 X D2 backcross generation, and a random survey of various inbred strains, suggest that the association between these two traits is due to genetic linkage, rather than to pleiotrophy or to chance. A major gene that inhibits susceptibility to ASs appears to be closely linked to the Ah locus. This gene has been designated Ias, for inhibition of ASs. A large portion of the genetic variability of AS susceptibility may be due to the segregation of Ias.     

Effects of neonatal thyroxine, genotype, and noise on the ear and audiogenic seizures.

T. N. Seyfried et al (1979) recently reported that the DBA/2J mouse genotype, which is innately susceptible to audiogenic seizures, has high neonatal levels of thyroxine (T?) and that neonatal injections of T? induced susceptibility in the C57BL/6J mouse. In the experiment, neonatal T? injections (20 μg) produced a temporary peripheral auditory dysfunction that appeared to be conductive in nature in the C57BL/6J mouse (n?=?106). A cochlear dysfunction was also seen in the DBA/2J mouse (n?=?17) and in the acoustically primed C57BL/6J mouse. Since a peripheral auditory threshold elevation in these latter groups of mice appears to be causally related to their susceptibility to audiogenic seizures, it is likely that at least a portion of the susceptibility that Seyfried et al reported was due to the effects of T? on the ear. (34 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.     

Noise and the young mouse: Genotype modifies the sensitive period for effects on cochlear physiology and audiogenic seizures.

Examined the correspondence between the critical period, during which acoustic trauma will profoundly alter subsequent auditory behavior, and the broader sensitive period, during which acoustic trauma is most damaging to cochlear functions in the young ear, using 133 C57BL/6 and 183 CBA mice (aged 12–54 days) as Ss. Ss were exposed to 2 min of 124-db octave band noise (8–26 kHz). A noninvasive electrocochleographic technique was used to assess cochlear microphonic (CM) and action potential (AP) thresholds in exposed Ss and nonexposed littermate controls. Noise had no effect on 12-day-old CBA Ss but produced a maximal threshold elevation at 30–36 days in 54-day-old Ss. Susceptibility to audiogenic seizures in exposed CBA Ss was greatest at the peak of the sensitive period for cochlear damage. 12-day-old C57BL/6 Ss were also unaffected by noise exposure; 36-day-old C57BL/6 Ss had maximal AP (23 db) and CM (17 db) threshold; elevations and 54-day-old C57BL/6 Ss had an 18-db elevation of the AP; and their CM was no longer affected. It is concluded that both genotypes have a sensitive period for the effects of noise trauma on CM and AP thresholds: CBA has a sensitive period for acoustic priming for audiogenic seizures, and C57BL/6 has a critical period for acoustic priming. (48 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Audiogenic seizures in curarized mice

Previous experiments have indicated that interference with somatosensory feedback from convulsive movements may lessen the severity of audiogenic seizures in susceptible rodents. For further investigation of this phenomenon, mice were partially immobilized with tubocurarine chloride to attenuate convulsive movements and somatosensory input associated with such movements. In Experiment 1, seizures of mice injected with .15 mg/kg were evaluated behaviorally and compared with seizures of saline-injected litter-mates. The likelihood of clonic-tonic seizures in curarized mice was as high as that of control mice, although convulsive movements were somewhat less violent and seizure fatalities were markedly reduced. In Experiment 2, seizures of mice given .25 mg/kg were evaluated with electroencephalography, and records were compared with those of controls. Despite the near absence of behavioral signs of convulsions, electroencephalograms of curarized mice showed that audiogenic seizures readily occurred. The findings suggest that audiogenic seizures are centrally "programmed" and do not require feedback from convulsive movements. However, it may be possible to disrupt the central "program" by introducing appropriate somatosensory input not normally encountered during audiogenic seizures.     

Propranolol-induced seizures in mice: the role of noradrenaline

The effects of some noradrenergic agents, phenobarbitone, diazepam and phenytoin on seizures produced by propranolol were investigated in mice. Isoprenaline and DL-threo-3,4-dihydroxyphenylserine (DOPS) effectively antagonized the seizures elicited by propranolol. Pargyline and imipramine significantly attenuated propranolol-induced seizures and also significantly potentiated the protecting effect of DOPS against the seizures. alpha-Methyl-p-tyrosine, disulfiram and reserpine significantly potentiated propranolol-elicited seizures. However, DOPS significantly antagonized the seizure-potentiating effects of alpha-methyl-p-tyrosine, disulfiram and reserpine. Phenylephrine, clonidine, prazosin, idazoxan, phenobarbitone, diazepam and phenytoin did not significantly alter propranolol-induced seizures. These results suggest that propranolol-induced seizures in mice may involve a noradrenergic mechanism mediated via central beta-adrenoceptors.     

Effects of misoprostol on pentylenetetrazol-induced seizures in mice

The effects of prostaglandin E-analogue misoprostol on the susceptibility to pentilenetetrazol (PTZ)-induced seizures were examined in mice. Misoprostol (200-800 micrograms/kg), given subcutaneously 45 min before the subconvulsive dose of PTZ (30 mg/kg, i.p) provoked dose-dependent clonic-tonic seizures (30 to 100%) and mortality in mice. At 300 g/kg, s.c., misoprostol pretreatment significantly (p < 0.05) lowered the onset latency to first convulsion as well as the latency to mortality induced by a convulsive dose of PTZ (60 mg/kg, i.p.). At this dose misoprostol was found to lower the CD50 and Ld50 values for PTZ by 21% and 36% respectively. The results suggest that prostaglandins are likely to lower the threshold for convulsions.     

Electron microscopic studies of the effect of audiogenic epileptic fits on the surface coat of cerebral capillaries of endothelium in mice]

In 25 eyes suffering from primary open angle glaucoma the facility of outflow was measured before and 1 to 3 months after surgery in consideration of the rigidity. Trabeculotomy improved the facility on an average of 0.14+/-0.02 to 0.28+/-0.03 units. This means that the outflow resistance is decreased from 10.58+/-1.34 to 4.31+/-0.45 units. The statistically highly significant improvement of the outflow conditions must be a consequence of the surgical opening in the trabecular meshwork as the sclera had been closed watertightly at the end of the trabeculotomy. The coefficient of rigidity (graphically determined by applanation tonometry and Schi?tz tonometry in recumbent position) was decreased from 0.0208+/-0.0010 to 0.0172+/-0.0008. This means that measuring the intraocular pressure postoperatively with a Schi?tz tonometer results in data which are 3.08+/-0.65 mm Hg lower than the actual pressure level.