Ketamine Rapidly Enhances Glutamate-Evoked Dendritic Spinogenesis in Medial Prefrontal Cortex Through Dopaminergic Mechanisms.
Biological Psychiatry January 8, 2021 Mingzheng Wu, Samuel Minkowicz, V. Dumrongprechachan et al. 96 citations
Ketamine rapidly enhances the formation of new dendritic spines in the mouse medial prefrontal cortex when glutamate uncaging triggers local plasticity, and this effect occurs within minutes—matching the drug's rapid antidepressant onset and preceding any overall increase in spine density. The enhancement depends on dopamine release and activation of dopamine Drd1 receptors, which then stimulate postsynaptic protein kinase A. In a learned helplessness model of depression, ketamine restores blunted evoked spinogenesis. Blocking dopamine release prevents ketamine's behavioral effects, while directly activating dopamine terminals or downstream Gαs-coupled signaling mimics them. Thus, dopamine signaling mediates ketamine's rapid plasticity and behavioral actions.