Generation and Characterization of Three Novel Mouse Mutant Strains Susceptible to Audiogenic Seizures

Abstract

The mechanisms of epileptogenesis after brain injury, ischemic stroke, or brain tumors have been extensively studied. As a result, many effective antiseizure drugs have been developed. However, there are still many patients who are resistant to therapy. The molecular and genetic bases regarding such drug-resistant seizures have been poorly elucidated. In many cases, heavy seizures are instigated by brain development malformations and often caused by gene mutations. Such malformations can be demonstrated in mouse models by generating mutant strains. One of the most potent mutagens is ENU (N-ethyl-N-nitrosourea). In the present study, we describe three novel mutant strains generated by ENU-directed mutagenesis. Two of these strains present a very strong epileptic phenotype triggered by audiogenic stimuli (G9-1 and S5-1 strains). The third mouse strain is characterized by behavioral disorders and hyperexcitation of neuronal networks. We identified changes in the expression of those genes encoding neurotransmission proteins in the cerebral cortexes of these mice. It turned out that the G9-1 strain demonstrated the strongest disruptions in the expression of those genes encoding plasma membrane channels, excitatory glutamate receptors, and protein kinases. On the other hand, the number of GABAergic neurons was also affected by the mutation. All three lines are characterized by increased anxiety, excitability, and suppressed motor and orientational–exploratory activities. On the other hand, the strains with an epileptic phenotype—G9-1 and S5-1ave reduced learning ability, and the A9-2 mice line retains high learning ability.

Keywords

• ENU-induced mutagenesis
• epileptiform activity
• audiogenic epilepsy
• behavioral experiments
• calcium ions
• signaling