The effect of acetyldexphenmetrazine and dexphenmetrazine on the susceptibility to audiogenic seizures in mice.

The antiepileptic effect of dexphenmetrazine (DP) and acetyldexphenmetrazine (ADP) was tested on audiogenic seizures in a 100% susceptible strain of mice. DP had no antiepileptic effect, however, it markedly suppressed the postparoxysmal motor inhibition. ADP had a distinct anticonvulsive effect--it suppressed the convulsive component of the seizure, leaving its running component unaffected. The results are compared with the effect of both drugs on electrographic epileptic phenomena in the turtle brain (Servít and Strejcková 1976).     

Amino acid neurotransmitter alterations in three sublines of Rb mice differing by their susceptibility to audiogenic seizures

The levels of inhibitory amino acids (Tau, Gly), or excitatory amino acids (Glu, Asp) and Gln, precursor of GABA, have been determined, under resting conditions, in 17 brain areas of 3 sublines of inbred Rb mice displaying different responses to an acoustic stimulus. Rb1 mice were clonictonic seizure-prone, Rb2 mice were clonic seizure-prone and Rb3 mice were seizure resistant. Profile of distribution in the brain of each one of these amino acids differed. Maximum to minimum level ratio was higher for Tau (3.8) than for Glu or Asp or Gln (2). The level of Gly was similar in 13 out of the 17 areas examined. Multiple inter-subline differences were recorded for each amino acid. These differences have been analyzed considering the seizure susceptibility or severity of the three Rb sublines. Common lower levels (approximately –20%: Rb1/Rb3, Rb2/Rb3) of Gln in Temporal Cortex may be implicated in seizure susceptibility. Seirure severity (Rb1/Rb2) seems to correlate, in some areas, with additional lower amounts of GABA already reported and, to a lower extent, of Asp (–19% in striatum, inferior colliculus and cerebellum), of Tau and Gly; a tendency for a rise in Gln content was observed in certain others (10–20% in olfactory bulb, thalamus, hypothalamus, substantia nigra, and frontal, temporal and occipital cortex). The data and correlations recorded provide guidelines for further investigations for synaptosomal and metabolic alterations in the three sublines of the same strain of Rb mice.Abbreviations used GABA 4-aminobutyrate - Tau taurine - Gly glycine - Asp aspartate - Glu glutamate - Gln glutamine - GEPR genetically epilepsy-prone rat - OB olfactory bulbs - OT olfactory tubercles - Sr striatum - Se septum - Hy hypothalamus - Hi hippocampus - Th thalamus - A amygdala - SC superior colliculus - IC interior colliculus - SN substantia nigra - FCx frontal cortex - TCx temporal cortex - OCx occipital cortex - C cerebellum - P pons - Ra raphe     

Confirmation of the influence of a Chromosome 7 locus on susceptibility to audiogenic seizures

Mouse strain differences in susceptibility to audiogenic seizures (AGS) are due to allelic differences at multiple genetic loci. Three loci that influence susceptibility to AGS have been mapped on Chromosomes (Chr) 12, 4, and 7 (Asp-1, Asp-2, and Asp-3, respectively). Here we report evidence that confirms linkage of Asp-3 to c on Chr 7 and parental effects on AGS susceptibility, but not genomic imprinting of Asp-3.     

Long-lasting effects of audiogenic seizures on neurotransmitter amino acids in Rb mice

The existence of long-lasting (15–18 h) alterations of neurotrasmitter amino acid levels following a single or repeated acoustic stimulations in audiogenic seizure-prone Rb1 and Rb2 mice and suizure-resistant Rb3 mice were investigated. The levels of glutamate, aspartate, glycine, taurine, and of some of their precursors: glutamine and serine were determined. Fourteen brain areas were examined. Alterations were found only in 6 brain areas (pons, olfactory bulbs, superior colliculus, inferior colliculus, olfactory tubercles and raphe). Most frequent occuring changes were observed in pons and olfactory tubercles. These changes concerned mainly the excitatory amino acids, glutamate, and aspartate. Alterations of taurine, glycine and serine were also recorded.Abbreviations GABA 4-aminobutyrate - Tau taurine - Gly glycine - Asp aspertate - Glu glutamate - Gln glutamine - Ser serine - OB olfactory bulbs - OT olfactory tubercles - Sr striatum - Se septum - Hy hypothalamus - Th thalamus - Hi hippocampus - A amygdala - SC superior colliculus - IC inferior colliculus - FC frontal cortex - C cerebellum - P pons medulla - Ra raphe - AA neurotransmitter amino acids - I inhibitory - E excitatory - SSL steady-state level Plesant memories of Lawrence Austin's sojourn in my group at Strasbourg gather upon me when I dedicate this article on this occasion for the contribution that Lawrence Austin has made for the cause of neurochemical researchers.     

Effect of neonatal 6-hydroxydopamine treatment on audiogenic seizures

Subcutaneous injection of 6-hydroxydopamine (6-OHDA) in newborn audiogenic rats resulted in an increase in convulsive seizure intensity and a decrease in norepinephrine concentration in the cerebral cortex and the spinal cord. In addition, norepinephrine concentration in the brainstem (pons-medulla) was increased. Dopamine concentration in all brain regions studied was unchanged. The results suggest that norepinephrine exerts its modulatory influence on convulsive seizures by an action in either the spinal cord, the cerebral cortex, or both.     

Genetic analysis of susceptibility to isoniazid-induced seizures in mice

Four sets of recombinant inbred lines of mice have been used to analyze genetic differences in acute toxicity of the drug, isonicotinic acid hydrazide. Standard inbred strains, their F₁ hybrids and recombinant inbred strains were all challenged with a single dose of the drug. The percent mortality of the different groups was analyzed to estimate heritability and the number of genes affecting resistance. The data indicated that resistance factors were dominant, heritability was moderate (.25-.37), and more than one gene was involved in each of four different sets of recombinant inbred lines. Possible approaches for identifying and mapping individual genes affecting resistance are discussed.     

Elevated sulfatide levels in neurons cause lethal audiogenic seizures in mice

Galactosylceramide (GalCer) and 3- O -sulfo-GalCer (sulfatide) are abundant sphingolipids in myelinating glial cells. However, low levels of GalCer and sulfatide have also been found in neurons, though their physiological role in these cells is unknown. Transgenic mice over-expressing UDP-galactose : ceramide galactosyltransferase (CGT) under control of the Thy1.2 promoter synthesize C18 : 0 fatty acid containing GalCer and sulfatide in neurons. Depending on the genetic background, these transgenic mice have a significantly reduced life span. Transgenic mice were extremely sensitive to sound stimuli and displayed lethal audiogenic seizures after relatively mild acoustic stimulation, i.e., key jangling. CGT-transgenic mice additionally over-expressing the adenosine 3'-phospho 5'-phosphosulfate : cerebroside sulfotransferase were more sensitive to audiogenic seizure induction than mice expressing only the CGT-transgene. This correlated with the higher sulfatide content in neuronal plasma membranes of the double-transgenic mice compared with CGT-transgenic mice, and strongly suggests that lethal audiogenic seizures are caused by elevated sulfatide levels in transgenic neurons. CGT-transgenic mice will be a useful model to further investigate how sulfatide affects functional properties of neurons.     

Cerebral, cerebellar, and brain stem gangliosides in mice susceptible to audiogenic seizures

Abstract— The quantitative and qualitative distribution of gangliosides was investigated in the cerebrum, cerebellum and brain stem of audiogenic seizure resistant (C57BL/6J) and susceptible (DBA/2J) mice at 21 days of age. The concentration of gangliosides (μg/unit weight) was higher in the DBA cerebrum and brain stem, but lower in the DBA cerebellum compared to the concentration in C57 mice. In general, the brain water content was lower in DBA mice than in C57 mice. The distributions of a number of gangliosides were found to be different between the two strains and the differences were often in the same direction across the three brain regions. The most consistant and significant difference in ganglioside pattern observed between the strains was the higher concentration of G_M1 in all three regions of the DBA brain. These results suggest that DBA mice have a more heavily myelinated CNS than C57 mice. The relationship of these observations to inherent audiogenic seizure susceptibility is discussed.     

Long lasting effects of audiogenic seizures on synaptosomal neurotransmitter amino acids in Rb mice

Long lasting alterations of synaptosomal amino acid neurotransmitters following a single or several audiogenic seizures and/or acoustic stimulations were investigated in six brain areas-olfactory bulbs (OB), amygdala (A), hippocampus (Hi), cerebellum (C), inferior colliculus (IC), ponsmedulla (P)- of three sublines of Rb mice: audiogenic seizure-prone Rb1 and Rb2, seizure-resistant Rb3. Changes in the synaptosomal levels of aspartate (Asp), glutamate (Glu), taurine (Tau), 4-amino butyrate (GABA), glycine (Gly) and some closely related precursors, serine (Ser) and glutamine (Gln), were recorded 15–18 hours after a single or multiple acoustic stimulations. Changes were more frequent, or larger, after polystimulation. Some alterations appeared to be attributable to an effect of the acoustic stress.In both seizure-prone sublines, after a single or repeated seizures, an increase in synaptosomal Asp was observed in IC. Decreases in Asp and Tau in OB and Ser in A, an increase in Gln in IC were only observed after repeated seizures, in Rb1 and Rb2 mice.Abbreviations used GABA 4-aminobutyrate - Tau taurine - Gly glycine - Ser serine - Asp aspartate - Glu glutamate - Gln glutamine - OB olfactory bulbs - A amygdala - Hi hippocampus - C cerebellum - IC interior colliculus - P pons Professeur Paul Mandel passed away on 6th October, 1992Special issue dedicated to Dr. Bernard W. Agranoff.     

Linear relationship between stimulus intensity and audiogenic seizures in inbred mice.

An examination of the manifestations of convulsive seizure activity in hundreds of inbred audiosensitive O'Grady mice exposed to auditory signals revealed that, apart from the maximal manifestation itself, the lag time prior to its obset is a suitable criterion for evaluation of the seizure response. Following exposure of a random population of 100 inbred mice to a fixed signal of average intensity which led to approximately 60% of tonic seizures, a scale of weighted values was designed. Animals responding with the maximal tonic seizures were subdivided further according to the lag time to the onset of response. Each group was assigned a value number. A scale of responses of individual mice, ranging from 1 to 10 points, approximately equivalent in terms of distribution of responses, was constructed thereby; individual results could be summed up for group totals. The statistical validity of the scale was proved in 583 typical inbred mice picked at random. Its usefulness was established when the evoked response of a group increased with increased stimulus intensity, the relationship being nearly linear between 69 and 85 dB, at 22 KHz. Group responses to signals of fixed sound pressure at frequencies ranging from 8 to 17 KHz were found to follow a bell-shaped response curve with peak seizure activity near 13 KHz, the frequency corresponding to the greatest mouse hearing acuity.     

Catechol-O-methyl transferase and monoamine oxidase activities in brains of mice susceptible and resistant to audiogenic seizures

The activities of catechol-O-methyl transferase (COMT), monoamine oxidase (MAO), and a methanol forming enzyme were studied in whole brain homogenates and in livers obtained from DBA/2J, C57B1/6J, and F₁ hybrid mice. DBA/2J mice are extremely susceptible to audiogenic seizures, where as C57B1/6J mice are resistant to sound-induced convulsions. C57B1/6J mice were found to have significantly higher brain levels of COMT, while MAO activities were not different in animals of these genotypes. No methanol forming activity was detected in animals of either strain. No differences were found in hepatic activities of either COMT or MAO. Pyrogallol was shown to protect DBA/2J animals against audiogenic seizures.