The Mechanism Underlying the Abnormal Expression of α-Synuclein in the Cortical Lesions of Patients With FCD Type IIb and TSC.

AIMS: This study aims to investigate the underlying mechanisms of abnormal expression of α-synuclein (α-syn) in cortical lesions of focal cortical dysplasia IIb (FCD IIb) and tuberous sclerosis complex (TSC).

METHODS

Cortical lesions of patients with FCD IIb and TSC were obtained during the surgery, FCD rats were generated by in utero X-ray radiation. Immunostaining, RT-PCR, Western blotting, and electroencephalography recording were conducted in this study. α-syn was intraventricularly injected; mTOR inhibitor (rapamycin) and glutamate transporter-1 (GLT-1) enhancer (ceftriaxone sodium) were intraperitoneally injected before the following experiments.

RESULTS

mTOR and p-mTOR expressed in the dysmorphic neurons, vimentin-positive balloon cells, and giant cells, whereas the mTOR/p-mTOR ratio was decreased in FCD IIb and TSC lesions. α-syn was decreased, while p-α-syn was increased in the cortex of FCD animals, whereas they were rescued by inhibition of mTOR with rapamycin. The expression of GLT-1 was decreased and modulated by rapamycin in FCD animals. Enhancement of the function of GLT-1 with ceftriaxone ameliorated α-synucleinopathy and seizure activities in FCD animals. Additionally, intracerebroventricular injection of α-syn exerted anti-seizure effects.

CONCLUSIONS

Our results showed that modulation of the mTOR/GLT-1 pathway ameliorated α-synucleinopathy and seizure activities in FCD, providing insights for understanding the epileptogenic mechanisms of FCD IIb and TSC.