Abstract
Our previous studies have shown an increase in the number of GABAergic and total neurons in the inferior colliculus (IC) of the genetically epilepsy-prone rat (GEPR-9) as compared to the non-seizing Sprague-Dawley (SD) rat. To determine whether an increase in neuron number in the IC is genetically associated with seizure behavior, seizing and non-seizing offspring of GEPR-9 and SD progenitor strains were studied as well as offspring from backcrosses made with f 1 and either GEPR-9 or SD rats. In addition, the ontogeny of seizure behavior was studied in seizing rats from these same backgrounds. The development of seizure behavior in GEPR-9s was shown to be dependent on age and the number of exposures to sound stimulus up until the age of 9 weeks. The F 1 and F 2 generations displayed different audiogenic seizure profiles than those of the two progenitor strains. In the F 1 generation, the ratio of seizing to non-seizing rats was always greater than 3:1, and the distribution of seizure scores was similar for males and females. In addition, the off-spring from backcrosses made with F 1 rats (high or low seizing) and GEPR-9s displayed maximal audiogenic response scores (ARS) of 9, a characteristic of the GEPR-9s used in this study. The results of these genetic studies indicate a polygenetic inheritance of this autosomal dominant trait of audiogenic seizure susceptibility. For the quantitative study of neuronal density in the IC, neurons were counted from cresyl violet-stained preparations from seizing and non-seizing F 1 and F 2 rats, backcrosses from different categories and age-matched SD rats. Statistically significant increases in the number of both small (70% increase) and medium-sized (14% increase) neurons occurred in the high seizing animals (ARS = 7–9) as compared to either the non-seizing F 2 or SD rats. In addition, a significant increase in the number of small neurons (77% increase) occurred in the high seizing offspring of the F 1 × GEPR-9 backcross as compared to that of the non-seizing offspring of the f 1 × SD back-cross. The data from 25 rats generated a 0.9 coefficient of linear correlation between ARS and the number of small neurons. The results from the anatomical studies suggest that the inheritance of audiogenic seizures appears to be closely linked to the increase in cell number. Therefore, the increase in cell number in the IC may be an important determinant of seizure behavior for GEPR-9s.
Highlights
The genetically epilepsy-prone rat (GEPR-9) exhibits severe generalized motor seizures in response to intense auditory stimuli14
We have previously shown that the inferior colliculus (IC) of adult GEPR-9s displays an increase in the total number of neurons and an increase in the number of GABAergic neurons as well*“
We have shown a significant increase in the levels of GABA in the central nucleus of the IC of GEPR-9s as compared to SD rats in a recent biochemical study”
Summary
The genetically epilepsy-prone rat (GEPR-9) exhibits severe generalized motor seizures in response to intense auditory stimuli. We have previously shown that the IC of adult GEPR-9s displays an increase in the total number of neurons and an increase in the number of GABAergic neurons as well*“. The increase in cell number within the IC is present prior to seizure activity because an increase in the total number of neurons has been demonstrated in GEPR9s at an age prior to the onset of seizures”. The increase in the total number of neurons and in the number of GABAergic neurons is not caused by seizure activity or exposure to an acoustic stimulus. A similar increase in the number of GABAergic neurons was observed in the hippocampal dentate gyrus of another model of genetic epilepsy’“, and interruption of the entorhina afferents to this structure will bIock seizures”. Increased numbers of GABAergic neurons could be a determinant of seizure behavior in some genetic models of epilepsy
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