AMPA receptor modulation in depression: from molecular mechanisms of plasticity to therapeutic translation
Pharmacological Reports June 12, 2026 Wojciech Ziemichód, Natalia Kajka, Klaudia Kister et al.
AMPA receptors, a key component of the glutamatergic system, are linked to the rapid antidepressant effects and synaptic plasticity observed after ketamine administration. Positive allosteric modulators of AMPA receptors, called AMPAkines, prolong receptor channel opening, enhance excitatory neurotransmission, and upregulate brain-derived neurotrophic factor (BDNF). Preclinical studies consistently show antidepressant-like effects of low-impact AMPAkines, which have a favorable safety profile compared to high-impact compounds that carry seizure risk. Preliminary clinical trials support these findings but are limited in scope. Significant translational hurdles remain, including a narrow therapeutic window, suboptimal pharmacokinetic properties, and limited predictive validity of animal models.