Subanesthetic doses of the NMDA antagonist ketamine enhance the excitability of the human motor cortex, as shown by progressive reductions in resting and active motor thresholds and increased muscle response amplitudes to transcranial magnetic stimulation. Before ketamine, mean resting motor threshold was 49% of maximum stimulator output; at the highest infusion level it fell to 42.6%. Active motor threshold dropped from 38% to 33%. Responses to electric stimulation were unchanged, indicating that ketamine specifically boosts excitatory cortical networks by increasing glutamatergic transmission at non-NMDA receptors, likely AMPA receptors, facilitating repetitive discharge of pyramidal neurons.
Adolescent mice given ketamine, which blocks NMDA receptors, showed lasting deficits in GABAergic inhibition in the medial prefrontal cortex as adults. Recordings from pyramidal neurons revealed reduced spontaneous and miniature inhibitory currents and altered paired-pulse ratios, indicating impaired presynaptic GABA release and diminished function of parvalbumin-positive interneurons. Spike-timing-dependent plasticity was also disrupted: spike pairings that normally cause depression instead induced potentiation. These results suggest that NMDA receptor hypofunction during adolescence produces enduring impairments in inhibitory transmission and shifts plasticity rules, providing mechanistic insight into circuit dysfunction relevant to neurodevelopmental disorders.
Under isoflurane anaesthesia, activating layer 5 pyramidal neurons in one hemisphere of the mouse sensorimotor cortex using chemogenetics (DREADDs) produced local wakefulness-like activity—shifting from slow-wave to tonic firing—and disrupted interhemispheric synchrony with the opposite hemisphere. However, this local activation did not reduce the depth of unconsciousness during deep anaesthesia or during transitions into or out of anaesthesia. Global layer 5 synchrony may be sufficient for anaesthesia-induced unconsciousness but is not necessary, at least under isoflurane. Local wakefulness-like activity in layer 5 cortex can occur during deep anaesthesia, highlighting the need to further explore local versus global aspects of anaesthesia-induced unconsciousness.