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  • Disruption of EAAT2-Mediated, Astrocytic Glutamate Buffering in Intractable Epilepsy

    Final Number:
    454

    Authors:
    Vishnu Anand Cuddapah; Natasha L Pacheco; Tracy Cartwright; G. Yancey Gillespie PHD; Curtis J. Rozzelle MD; Jeffrey P. Blount MD; Kristen O. Riley MD; Michelle L Olsen

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: Approximately one-third of patients with epilepsy experience seizures that are refractory to medical treatment. While nearly all anti-epileptic drugs target neuronal function, there is emerging evidence that non-neuronal cells may also contribute to epilepsy. In the normal brain, astrocytes play an integral role in dampening neuronal excitability by clearing glutamate from the extracellular space, largely through excitatory amino-acid transporter 2 (EAAT2). Here we assessed astrocytic glutamate buffering in 2 cases of refractory epilepsy.

    Methods: Patients selected in this study underwent surgical interventions for treatment of refractory epilepsy following an extensive non-invasive evaluation in which EEG, MRI, and functional data were presented in a clinical epilepsy planning conference. A consensus opinion of the region of ictal onset was generated and used to guide surgical procedures. Regions that were implicated in epileptogenesis were designated “more epileptogenic” while adjacent regions that were resected due to delayed spread of epileptic activity were deemed “less epileptogenic”. Comparing “less” and “more” epileptogenic tissue in each patient, we assessed the ability of astrocytes to remove glutamate from the extracellular space using measurements of [3H]-glutamate uptake and Western blotting. All protocols and procedures were approved by the University of Alabama at Birmingham Institutional Review Board.

    Results: We find that the glutamate buffering capacity of astrocytes in highly epileptogenic tissue is impaired due to loss of EAAT2. Along with EAAT2 downregulation, we also find downregulation of other proteins involved in glutamate homeostasis including Kir4.1, an astrocytic K+ channel, and glutamine synthetase, involved in glutamate metabolism.

    Conclusions: These data indicate that disruption in astrocyte-mediated glutamate clearance may contribute to refractory epilepsy. Thus, investigation of novel anti-epileptic drugs targeting astrocytic dysfunction may lead to better medical management of epilepsy.

    Patient Care: Approximately one-third of patients with epilepsy experience seizures that are refractory to medical treatment. Using a neurosurgical approach, we isolated tissue from patients with refractory epilepsy to determine non-neuronal mechanisms of epileptogenesis. We find that astrocytes may play a critical role in refractory epilepsy. Thus, future anti-epileptic drugs should focus on astrocytic targets to decrease disease burden in patients refractory to traditional therapies.

    Learning Objectives: By the conclusion of this poster, participants should be able to: 1) Explain how astrocytic glutamate buffering may be impaired in refractory epilepsy, 2) Describe a method for measurement of astrocytic glutamate uptake, and 3) List proteins involved in astrocytic glutamate metabolism.

    References:

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