Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.
Ketamine's rapid and sustained antidepressant and anxiolytic effects depend on neuronal activity in the infralimbic prefrontal cortex (IL-PFC). Inactivating the IL-PFC in rodents completely blocked the behavioral effects of systemic ketamine, while direct microinfusion of ketamine into the IL-PFC reproduced those effects. Optogenetic stimulation of the IL-PFC alone also produced rapid, long-lasting antidepressant and anxiolytic effects, which were linked to increased number and function of spine synapses in layer V pyramidal neurons. The findings demonstrate that activating the IL-PFC is sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to those from systemic ketamine.
Ketamine's rapid antidepressant effects depend on GluN2B-containing NMDA receptors on somatostatin-expressing (Sst) interneurons in the medial prefrontal cortex (mPFC). In mice, a single subanesthetic dose of ketamine reduced NMDA-induced burst firing of Sst-interneurons, decreased inhibitory transmission, and increased excitatory transmission in layer V pyramidal neurons, reversing behavioral deficits caused by chronic unpredictable stress. These effects were absent in mice lacking GluN2B from Sst-interneurons. The findings identify Sst-interneurons as the initial cellular trigger for ketamine's synaptic and behavioral actions, supporting the disinhibition hypothesis whereby ketamine disinhibits pyramidal neurons via GluN2B-NMDARs on Sst-interneurons, activating mTOR signaling and enhancing synaptic function.