ALG13 Deficiency and Epilepsy-Related Cognitive Impairment: Role of the DDIT4-Mediated PI3K/AKT/mTOR Pathway

OBJECTIVE: This study aimed to investigate the impact of ALG13 deficiency on cognitive function in mice. METHODS: Cognitive behavior in Alg13 knockout (KO) mice was assessed using the IntelliCage system (free exploration, nosepoke learning, spatial learning, and reversal learning) and the Smart 3.0 system (open-field activity, novel object recognition, and spatial object recognition). Social cognition was evaluated through three-chamber sociability, novelty preference, and social recognition memory tests. RNA sequencing and bioinformatic analyses were conducted to explore potential molecular mechanisms. RESULTS: When housed separately, Alg13 KO mice exhibited impaired free exploration, nosepoke learning, and spatial reversal learning compared to wild-type (WT) controls; however, co-housing eliminated these differences, with no significant disparities in free exploration, nosepoke learning, spatial learning, or spatial reversal learning. Notably, Alg13 KO mice had significantly lower error rates in spatial position learning and spatial position reversal learning. In behavioral analyses using Smart 3.0 tracking, Alg13 KO mice were found to exhibit diminished locomotor activity in the open-field task, impaired novel object recognition, and reduced spatial novelty exploration. In social cognition tests, both WT mice and Alg13 KO mice showed a preference for novel stimuli, but WT mice showed superior learning abilities compared to Alg13 KO mice. Furthermore, downregulation of the hub gene Ddit4 and activated PI3K/AKT/mTOR signaling pathway were identified in RNA sequencing. CONCLUSION: ALG13 deficiency results in cognitive impairment in mice, potentially mediated by dysregulation of the DDIT4-PI3K/AKT/mTOR signaling pathway.