Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine.
Steven F GriecoXin QiaoKevin G JohnstonLujia ChenRenetta R NelsonCary LaiTodd C HolmesXiangmin XuPublished in: Translational psychiatry (2021)
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. 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. 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.
Keyphrases
- pain management
- major depressive disorder
- low dose
- prefrontal cortex
- spinal cord
- end stage renal disease
- liver failure
- randomized controlled trial
- chronic kidney disease
- clinical trial
- drug delivery
- spinal cord injury
- intensive care unit
- dna methylation
- insulin resistance
- physical activity
- hepatitis b virus
- chronic pain
- combination therapy
- skeletal muscle
- aortic dissection
- mechanical ventilation
- patient reported
- replacement therapy
- wild type