Ketamine rapidly enhances glutamate-evoked dendritic spinogenesis in medial prefrontal cortex through dopaminergic mechanisms

ABSTRACT Background Ketamine elicits rapid onset antidepressant effects in clinically depressed patients, through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity. Methods Here, we use 2-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex (mPFC), directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combine pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes. Results We find that ketamine rapidly enhances glutamate-evoked spinogenesis in mPFC, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through Drd1 receptor activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic Protein Kinase A (PKA) activity. Furthermore, ketamine’s behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals, or postsynaptic Gαs-coupled cascades in mPFC. Conclusions Our findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.