The effect of sensory deprivation and mutant gene dosage on seizures and sustained attention in a mouse model of absence epilepsy.

Abstract

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a frequent comorbidity in epilepsy, particularly absence epilepsy, but the mechanistic links between these conditions remain poorly understood. We evaluated attention and seizure susceptibility in a genetically tractable mouse model carrying heterozygous and homozygous mutations in Cacng2, a gene encoding an AMPA receptor-associated membrane protein implicated in both epilepsy and deficits in sustained attention. METHODS: Mice underwent sustained attention testing using the 5-Choice Serial Reaction Time Task (5-CSRTT) and electroencephalographic monitoring for spike-wave seizures. The effect of early-life sensory deprivation through whisker trimming on both seizure activity and attention was also assessed. RESULTS: There was a gene dose-dependent impairment in 5-CSRTT performance, with homozygous mutants showing significantly lower accuracy and higher incorrect response rates than wild-type littermates, and heterozygous mice had significantly greater premature responses than both wild type and homozygous mutant mice. Whisker trimming increased seizure duration in heterozygous mice but paradoxically trended toward an improvement in attention performance with reduced impulsivity. These findings suggest that attention deficits in this model may arise independently of seizure burden. CONCLUSIONS: Compared to other preclinical models, Cacng2 mutant mice uniquely combine a human-relevant genetic mutation with spontaneous absence seizures and quantifiable deficits in sustained attention. The model thus provides a powerful platform for investigating the neurobiological intersection of epilepsy and ADHD and for evaluating potential therapeutic interventions. Our results underscore the need to disentangle seizure-driven effects from genetically mediated comorbid cognitive deficits in epilepsy and ADHD.