Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation

Why is ketamine an antidepressant? A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science, this issue p. eaat8078; see also p. 129 Spine formation in the prefrontal cortex is central to the long-term antidepressant effects of ketamine. INTRODUCTION Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them. RATIONALE Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment. RESULTS The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior. CONCLUSION Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission. Prefrontal spinogenesis is required for sustaining—but not inducing—ketamine’s effects on behavior and circuit function. (A) Complementary effects of stress and ketamine on spine remodeling, circuit function, and behavior. (B) The time course of changes indicates that spine formation is not required for inducing these effects initially. * indicates significantly different post hoc contrast, Holm-Bonferroni corrected (P < 0.002, P < 0.0006, and P < 0.05 for spine formation, immobility, and ensemble event frequency, respectively). NS, not significant. Error bars indicate SEM. (C) Optogenetic deletion of newly formed spines interferes with the long-term maintenance of these effects. Rx, treatment. The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.