One Disorder, Two Brains: Challenges in Modeling Epilepsy and Associated Movement Disorders in Mice

Modeling epileptic syndromes co-occurring with movement disorders in mice often fails to fully recapitulate human phenotypes due to distinct gene-specific and anatomical mechanisms. This review categorizes these translational barriers into three primary groups. First, ortholog heterotopia and heterochrony drive spatiotemporal shifts in gene expression, causing orthologs to activate at disparate developmental stages or within different cell populations across species. Second, molecular redundancy and compensation obscure phenotypes through the upregulation of alternative proteins in response to target protein suppression, the activation of modifier genes, or neural network rewiring. Third, structural variations in striatal anatomy fundamentally alter corticostriatal loop functioning. Characterizing these divergent mechanisms is essential for improving the predictive validity of preclinical models and advancing targeted therapies.