The antidepressant effects of ketamine require vascular endothelial growth factor (VEGF) signaling through its receptor Flk-1 in excitatory neurons of the medial prefrontal cortex (mPFC). Deleting VEGF or Flk-1 from forebrain excitatory neurons, or blocking VEGF in the mPFC, prevented ketamine's behavioral effects in mice. Infusing VEGF directly into the mPFC produced rapid antidepressant-like actions similar to ketamine, but these were blocked by Flk-1 deletion. Local knockdown of Flk-1 in adult mPFC excitatory neurons also blocked ketamine's effects. Additionally, blocking neuronal VEGF signaling prevented the neurotrophic and synaptogenic actions of ketamine. Neuronal VEGF-Flk-1 signaling in the mPFC is essential for ketamine's rapid antidepressant actions.
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.
Focal temporal lobe seizures in humans often cause loss of consciousness accompanied by cortical slow waves similar to deep sleep. Previous rat studies under anesthesia suggested that reduced subcortical arousal depresses cortical function, but could not link conscious behavior to physiology. In an awake mouse model, electrically induced hippocampal seizures impaired behavioral responses to sounds, triggered cortical slow waves, and reduced mean high-frequency cortical activity. Behavioral responses depended on cortical acetylcholine release at two timescales: slow state-related decreases correlated with overall impairment, while fast phasic release corresponded to variable spared or impaired responses per stimulus. These results establish a strong link between decreased cortical arousal and impaired consciousness during focal seizures.
Ketamine produces sustained antidepressant effects in mice by first decreasing then increasing the activity of GABA neurons in the medial prefrontal cortex. Calcium recordings showed an initial transient decrease in GABA neuron activity (phase 1, under 30 minutes) followed by an increase (phase 2, after 60 minutes), alongside a lasting enhancement of glutamatergic activity (30-120 minutes). Chemogenetic inhibition of GABA interneurons during phase 2 or before behavioral tests blocked ketamine's antidepressant actions. The findings indicate that time-dependent modulation of GABAergic activity is required for ketamine's sustained antidepressant-like responses, suggesting that enhancing GABAergic plasticity and function may be a promising therapeutic target.