Neuroprotective role of GLT-1/EAAT2 in glutamate-induced excitotoxicity

Glutamate-mediated excitotoxicity represents a common pathomechanism in neurological disorders. As the predominant glutamate transporter in the central nervous system, glutamate transporter 1 (GLT-1, known as EAAT2 in humans) plays a crucial role in maintaining glutamate homeostasis and preventing excitotoxicity through its Na⁺-dependent transport mechanism. Key functions of GLT-1 include reducing extracellular glutamate concentration, regulating calcium homeostasis, suppressing oxidative stress, preserving mitochondrial integrity, and modulating neuroinflammatory processes by limiting microglial activation. This review systematically examines the role of GLT-1 in cerebral ischemia/reperfusion injury, neurodegenerative diseases, epilepsy, chronic pain, and psychiatric disorders. Furthermore, the therapeutic potential of GLT-1 is explored, encompassing pharmacological activators (e.g., ceftriaxone), gene therapy approaches (e.g., adeno-associated virus (AAV)-mediated GLT-1 overexpression), and non-coding RNA-based strategies. Future research should focus on elucidating the precise regulatory networks of GLT-1 and developing targeted therapies with enhanced specificity and minimal off-target effects.