Background: A variety of evidence suggested that an imbalance in excitatory and inhibitory neurotransmission
could be one of the pathophysiological mechanisms underlying the occurrence and progression of
seizures. Understanding the causes of this imbalance may provide essential insight into the basic mechanisms of
epilepsy and may uncover novel targets for future drug therapies. Accordingly, GABA is the most important
inhibitory neurotransmitter in the CNS and its receptors (e.g., GABAARs) can still be relevant targets of new
antiepileptic drugs (AEDs).
Methods: Up to now, a variety of modulating agents that directly or indirectly act at GABAARs have been proposed
for restoring the physiological balance of excitation and inhibition in the epileptogenic brain. While benzodiazepine,
barbiturates and allosteric modulators of GABAARs are well-known for their anticonvulsant effect,
new compounds as modulators of chloride homeostasis or phytocannabinoids are not completely unraveled and
their antiepileptic action is still matter of debate. In addition, several inflammatory mediators as cytokines and
chemokines play an important role in the modulation of GABAAR function, even if further research is needed to
translate these new findings from the bench to the bedside. Finally yet importantly, a new frontier in epilepsy
research is represented by the observation that specific small noncoding RNAs, namely miRNAs, may regulate
GABAAR function paving the road to therapeutic approaches based on the modulation of gene expression.
Conclusion: Here, we review key physiological, neuropathological and functional studies that altogether
strengthen the role of modulation of GABAARs function as therapeutic target. The discovery of the novel molecular
mechanisms underlying the GABAergic transmission in epilepsy represents another heavy piece in the “epileptic
puzzle”. Even if GABAAR is an old story in the pharmacology of the epilepsy, the reviewed findings suggest
that new players in the scenario need to be considered.