Pathophysiology associated with a single gene (MASS1) mutation underlying the robust audiogenic seizure phenotype in Frings mice

The audiogenic seizure (AGS)-susceptible Frings mouse is a genetic model for generalized reflex epilepsy. The single genetic locus responsible for the AGS phenotype in Frings mice, named monogenic audiogenic seizure-susceptible MASS1, has recently been identified but the function of MASS1 is unknown. One goal of the present investigation was to identify the pathophysiology from the Frings MASS1 mutation that leads to the development of the robust AGS-susceptible phenotype. We hypothesized that the Frings MASS1 mutation produces cochlear dysfunction leading to hyperexcitability in the inferior colliculus, and that the MASS1 mutation may exert direct effects on intrinsic neuroexcitability in the brain. The hypothesis was investigated through studies that mapped the AGS network in Frings mice, measured auditory function, examined tonotopic response domains in the inferior colliculus and measured electroconvulsive seizure thresholds (ECT) in mice with and without the MASS1 mutation. Neuronal activation from AGS in Frings mice, as measured by seizure-induced expression of the immediate early gene c-Fos, was limited to a brainstem seizure network. This suggests that an expanded neuronal network is not involved in the robust AGS phenotype. Measuring auditory brainstem responses revealed that the MASS1 mutation produces a moderate and relatively stable early onset hearing impairment. Sound-induced c-Fos expression in the inferior colliculus was used to examine tonotopic neuronal responses to sub-AGS threshold, tone stimulations. The Frings mice displayed significant tonotopic hyper-responsiveness in the inferior colliculus to the subthreshold tone stimulations. This suggests that abnormal neuronal circuits develop in the inferior colliculus as a result of the early onset hearing impairment from the MASS1 mutation. Behavioral ECT testing was used to measure regional neuroexcitability (brainstem, forebrain and limbic structures) associated with the MASS1 mutation. The ECT tests demonstrated that the MASS1 mutation significantly lowered the electroconvulsive threshold in the brainstem and lowered resistance to seizure spread. The studies in this dissertation revealed that the Frings MASS1 mutation produces a moderate and stable hearing impairment that results in a neuronal hyper-responsiveness in the inferior colliculus. These auditory defects, combined with a significantly lowered threshold for brainstem seizures, produce the particularly robust AGS phenotype in the Frings mice.