Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA. manoela_fogaca@urmc.rochester.edu.
2 papers in the library · 23 citations · publishing 2025-2026
Ketamine produces sustained antidepressant effects in mice by first decreasing and later increasing the activity of GABA neurons in the medial prefrontal cortex. Calcium recordings showed an initial transient drop in GABA neuron activity lasting about 60 minutes, alongside a brief rise in excitation/inhibition balance and a longer-lasting increase in glutamatergic activity from 30 to 120 minutes. Previous ketamine treatment enhanced GABA neuron activity during behavioral tests 24 and 72 hours later. Chemogenetically inhibiting GABA interneurons during the later surge of activity or just before those tests blocked ketamine's behavioral effects. Thus, time-dependent modulation of GABAergic activity is necessary for ketamine's lasting antidepressant-like actions, pointing to GABAergic plasticity as a target for new antidepressants.
A negative allosteric modulator of α5-GABA A receptors, Basmisanil (BSM), produces rapid and sustained improvements in motivation, pleasure-seeking, and active coping behaviors in mice, similar to ketamine but without its side effects. BSM activates specific cell types in the medial prefrontal cortex (mPFC) and engages signaling pathways (Erk, Akt-mTOR) that boost synaptic proteins for both glutamatergic and GABAergic function. It also reverses stress-induced impairments in memory and social interaction. Early activation of pyramidal neurons in the mPFC is necessary for BSM's rapid effects, while later GABAergic adaptations sustain long-term benefits, restoring excitation-inhibition balance and highlighting GABAergic targets for stress-related disorders.