AMPA receptor modulation in depression: from molecular mechanisms of plasticity to therapeutic translation

The glutamatergic system, particularly N-methyl-D-aspartate (NMDA) receptors, has long been a significant focus of research into new strategies for treating depression, and the clinical success of ketamine, an NMDA receptor antagonist, has been a significant breakthrough. In parallel, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, another key component of the glutamatergic system, have been studied for decades, and renewed interest stems from evidence linking their activation to the rapid antidepressant effects and synaptic plasticity observed after ketamine administration. Among pharmacological agents targeting AMPA receptors, the class of positive allosteric modulators, AMPAkines, has attracted particular interest. These compounds act by prolonging AMPA receptor channel open time, thereby enhancing excitatory neurotransmission and upregulating brain-derived neurotrophic factor (BDNF) expression. Preclinical studies consistently demonstrated antidepressant-like effects of low-impact AMPAkines, which offer a favorable safety profile in contrast to high-impact compounds that carry seizure risk. Although preliminary clinical trials support these findings, their limited scope highlights persistent translational challenges. These include a narrow therapeutic window, suboptimal pharmacokinetic properties, and the limited predictive validity of animal models. AMPAkines thus represent a potentially promising class of rapid-acting antidepressants, although significant translational hurdles remain. This narrative review aims to synthesize evidence on the role of AMPA receptors in neuroplasticity, the therapeutic potential of AMPA receptor modulators (AMPAkines) in influencing neuroplasticity, and their potential therapeutic applications in depression.