| dc.description.abstract | The mechanism underlying ketamine’s rapid and sustained antidepressant action remains incompletely understood. In this dissertation, we investigated ketamine’s modulation of excitatory and inhibitory synaptic transmission and explored the implications of our findings for the treatment of psychiatric and neurodevelopmental disorders. At excitatory synapses, we found that homeostatic plasticity induced by ketamine is mechanistically distinct from classic Hebbian plasticity, and these processes may co-occur at the synaptic level. As learning and memory are thought to be encoded by Hebbian long-term potentiation, this finding provides a synaptic basis for the lack of effect of low-dose ketamine on learning and memory in clinical populations. We also demonstrated that direct agonism of the TrkB receptor, which is stimulated in the signaling cascade activated by ketamine in excitatory neurons, was sufficient to recapitulate excitatory synaptic potentiation similar to ketamine. However, direct TrkB agonism failed to replicate ketamine’s robust behavioral effects. Our investigation of inhibitory neurotransmission revealed that ketamine induced an acute but transient reduction of inhibitory activity that appears to be mechanistically distinct from ketamine’s action at excitatory synapses. BDNF-TrkB signaling alone could not replicate this transient disinhibition at inhibitory synapses, but it was required for restoration of the homeostatic set point of inhibitory activity after ketamine treatment. In Mecp2 knockout mice, which model the neurodevelopmental disorder Rett syndrome, loss of MeCP2 function did not influence the response to ketamine at excitatory synapses. However, Mecp2 knockout mice exhibited a selective impairment of homeostatic recovery after ketamine treatment at inhibitory synapses, suggesting a role of MeCP2 in buffering against sustained inhibitory plasticity. Taken together, our findings reveal new mechanistic insight into the molecular underpinnings of ketamine’s action at both excitatory and inhibitory synapses. This knowledge provides important perspectives for the ongoing investigation into the safety and efficacy of ketamine for therapeutic intervention in psychiatric and neurodevelopmental disorders. | |
