CNS neuroscience & therapeutics · 2025
Liver X Receptor Beta Regulates Glial Dynamics and Cortical Network Remodeling in a Freezing Lesion-Cortical Dysplasia Model.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zhang Zhi, Du Di, Song Min, Li Jie, Dong Xinning, Mei Yiwen, Zhang Jinwei, Zhang Ming, Ma Yuan, Yu Sixun, Shu Haifeng, Chen Xin
Аннотация
BACKGROUND: Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, characterized by cortical malformations and aberrant neuronal-glial interactions. Recently, the role of Liver X Receptor Beta (LXRβ) in neurodevelopment has attracted considerable attention, although its involvement in FCD pathogenesis remains unclear.
METHODS: We established a freezing lesion-cortical dysplasia (FL-CD) model in neonatal mice to mimic the pathological features of FCD. We evaluated the expression of LXRβ and its downstream target, brain lipid-binding protein (BLBP), using immunohistochemistry and Western blot analysis. LXRβ activation and inhibition were pharmacologically modulated to assess their effects on glial migration, differentiation and cortical electrophysiology. Electroencephalogram (EEG) recordings were analyzed for power spectral density and functional connectivity to further investigate alterations in cortical network activity.
RESULTS: LXRβ and BLBP were significantly downregulated in the lesion cortex during early developmental stages. Activation of LXRβ reduced gliosis, promoted astrocytic differentiation, and modified cortical oscillatory activity, as evidenced by enhanced α power and gamma band functional connectivity, along with adjustments in the theta/beta ratio. In contrast, inhibition of LXRβ exacerbated gliosis and disrupted cortical network synchronization.
CONCLUSION: Our findings demonstrate that LXRβ plays a critical role in regulating glial migration, differentiation and cortical network remodeling in the FL-CD model. Pharmacological modulation of LXRβ may offer a novel therapeutic strategy for restoring neural circuit stability in FCD, highlighting its potential as a molecular target for intervention in drug-resistant epilepsy.
METHODS: We established a freezing lesion-cortical dysplasia (FL-CD) model in neonatal mice to mimic the pathological features of FCD. We evaluated the expression of LXRβ and its downstream target, brain lipid-binding protein (BLBP), using immunohistochemistry and Western blot analysis. LXRβ activation and inhibition were pharmacologically modulated to assess their effects on glial migration, differentiation and cortical electrophysiology. Electroencephalogram (EEG) recordings were analyzed for power spectral density and functional connectivity to further investigate alterations in cortical network activity.
RESULTS: LXRβ and BLBP were significantly downregulated in the lesion cortex during early developmental stages. Activation of LXRβ reduced gliosis, promoted astrocytic differentiation, and modified cortical oscillatory activity, as evidenced by enhanced α power and gamma band functional connectivity, along with adjustments in the theta/beta ratio. In contrast, inhibition of LXRβ exacerbated gliosis and disrupted cortical network synchronization.
CONCLUSION: Our findings demonstrate that LXRβ plays a critical role in regulating glial migration, differentiation and cortical network remodeling in the FL-CD model. Pharmacological modulation of LXRβ may offer a novel therapeutic strategy for restoring neural circuit stability in FCD, highlighting its potential as a molecular target for intervention in drug-resistant epilepsy.