Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamin
Chen, L., Grieco, S. F., Holmes, T. C., Johnston, K. G., Lai, C., Nelson, R. R., Qiao, X., Xu, X.
This rodent study (n=50) investigated the signaling pathways associated with the rapid antidepressant effects of ketamine (10mg/kg) and found a novel neural plasticity-based mechanism implicated in its acute and sustained effects.
Abstract
Introduction: Subanesthetic ketamine evokes rapid antidepressant effects in human patients that persist long past ketamine's chemical half-life of ~2 h. Ketamine's sustained antidepressant action may be due to modulation of cortical plasticity.Methods: To determine if the ketamine-mediated amelioration of depression-like behaviors depends on NRG1/ErbB4 signaling in PV inhibitory interneurons, we tested the antidepressant effects of ketamine in the FST using mice, by manipulating NRG1/ErbB4 signaling.Results: We find that ketamine ameliorates depression-like behavior in the forced swim test in adult mice, and this depends on parvalbumin-expressing (PV) neuron-directed neuregulin-1 (NRG1)/ErbB4 signaling. Ketamine rapidly downregulates NRG1 expression in PV inhibitory neurons in mouse medial prefrontal cortex (mPFC) following a single low-dose ketamine treatment. This NRG1 downregulation in PV neurons co-tracks with the decreases in synaptic inhibition to mPFC excitatory neurons for up to a week. This results from reduced synaptic excitation to PV neurons, and is blocked by exogenous NRG1 as well as by PV targeted ErbB4 receptor knockout.Discussion: Thus, we conceptualize that ketamine's effects are mediated through rapid and sustained cortical disinhibition via PV-specific NRG1 signaling. Our findings reveal a novel neural plasticity-based mechanism for ketamine's acute and long-lasting antidepressant effects.