Balancing Excitatory and Inhibitory Neurotransmission in Epilepsy: Therapeutic Role of Gabaergic and Glutamatergic Modulation – a Review
Year: 2026
Type: article
Abstract: Epilepsy is a chronic neurological disorder marked by recurrent, unprovoked seizures arising from aberrant hypersynchronous neuronal firing within cortical and subcortical networks. A central framework explaining seizure generation is the excitatory–inhibitory imbalance hypothesis, wherein reduced γ-aminobutyric acid (GABA)–mediated inhibition and excessive glutamate-driven excitation disrupt neuronal homeostasis (Treiman, 2001; Meldrum, 2002). GABA acts as the principal inhibitory neurotransmitter through GABAAA and GABABB receptor systems, while glutamate is the primary excitatory neurotransmitter acting via NMDA, AMPA, and kainate receptors (Scharfman, 2007). Modern antiepileptic drugs (AEDs) strategically target these pathways: GABAergic therapies enhance inhibitory tone through receptor potentiation, reuptake inhibition, or increased synaptic GABA availability, whereas glutamatergic modulators suppress pathologic excitation by antagonizing NMDA/AMPA receptors or reducing presynaptic glutamate release (Macdonald & Rogawski, 2008). This review systematically compares both therapeutic strategies, highlighting their mechanisms of action, clinical efficacy across seizure types, pharmacological limitations, and safety considerations. Furthermore, emerging evidence from molecular, genetic, and synaptic studies outlines new therapeutic avenues, including receptor-subtype–selective modulators, synapse-specific glutamate inhibition, and combined GABA–glutamate targeted approaches designed to address drug-resistant epilepsy (Pitkänen et al., 2016; Baulac & Pitkänen, 2020). Collectively, understanding the differential and complementary roles of ABAergic and glutamatergic modulation provides a foundation for precision-based antiepileptic therapy and the development of next-generation interventions.
Authors: Bhardwaj Vaibhav*, Dr. Roy R. K.
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7161378235
FWCI:
Cites:
Cited by:
Related to: