Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy

NEUROBIOLOGY OF DISEASE

卷:157

Article

Peterson, Allison R.¹  Garcia, Terese A.¹  Cullion, Kyle²  Tiwari-Woodruff, Seema K.¹  Pedapati, Ernest, V^2,3  Binder, Devin K.¹ 

[1] Univ Calif Riverside, Ctr Glial Neuronal Interact, Sch Med, Div Biomed Sci, Riverside, CA 92521 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Child & Adolescent Psychiat, Cincinnati, OH 45229 USA

[3] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA

关键词: Epilepsy;    Glutamate transporter-1;    GLT-1;    AAV;    Kainic acid;    Seizure;    Astrocyte;   

DOI  :  10.1016/j.nbd.2021.105443

来源: Elsevier

【 摘 要 】

Astrocytic glutamate transporters are crucial for glutamate homeostasis in the brain, and dysregulation of these transporters can contribute to the development of epilepsy. Glutamate transporter-1 (GLT-1) is responsible for the majority of glutamate uptake in the dorsal forebrain and has been shown to be reduced at epileptic foci in patients and preclinical models of temporal lobe epilepsy (TLE). Current antiepileptic drugs (AEDs) work primarily by targeting neurons directly through suppression of excitatory neurotransmission or enhancement of inhibitory neurotransmission, which can lead to both behavioral and psychiatric side effects. This study investigates the therapeutic capacity of astrocyte-specific AAV-mediated GLT-1 expression in the intrahippocampal kainic acid (IHKA) model of TLE. In this study, we used Western blot analysis, immunohistochemistry, and longterm-video EEG monitoring to demonstrate that cell-type-specific upregulation of GLT-1 in astrocytes is neuroprotective at early time points during epileptogenesis, reduces seizure frequency and total time spent in seizures, and eliminates large behavioral seizures in the IHKA model of epilepsy. Our findings suggest that targeting glutamate uptake is a promising therapeutic strategy for the treatment of epilepsy.