CD44 Predisposes the Epileptogenesis of Cortical Tubers by Regulating CASK and Acts as a Potential Biomarker to Identify Epileptogenic Tuber in Tuberous Sclerosis Complex.
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BACKGROUND: Tuberous sclerosis complex (TSC) is characterized by developmental delay and intractable epilepsy, with multiple cortical tubers in the brain. However, the mechanism underlying epileptogenesis within these tubers remains unclear. METHODS: RNA sequencing (RNA-seq) analysis of resected human cortical tubers identified differential CD44 expression as a potential contributor to TSC epilepsy. By analyzing clinical characteristics, resected brain tissues, 18F-fludeoxyglucose PET images, cultured cortical neurons, and neocortical seizure animal models, the effect of CD44 on the epileptogenesis of cortical tubers was investigated. RESULTS: Increased CD44 expression was found in human Epi tubers compared with non-Epi tubers and closely correlated with the clinical characteristics of Epi tubers. CD44 activation increased neocortical seizure susceptibility and aggravated cortical pyramidal neuronal excitatory/inhibitory (E/I) imbalance. CASK was selected as the downstream target of CD44 using RNA-seq. Anti-CD44 monoclonal antibodies rescued the E/I imbalance in resected Epi tubers, and CD44 activation rescued the decreased firing frequency and increased action potential threshold induced by CASK inhibition. The CD44-CASK pathway exhibited diagnostic potential for identifying Epi tubers and predicting surgical outcomes via ROC analysis. CONCLUSION: CD44 activation predisposes cortical tubers to epileptogenesis, and could be a potential biomarker for identifying Epi tubers and predicting surgical outcomes in TSC patients.