R.N. Moda-Sava, M.H. Murdock, P.K. Parekh, R.N. Fetcho, B.S. Huang, T.N. Huynh, J. Witztum, D.C. Shaver, D.L. Rosenthal, E.J. Alway, K. Lopoz, Y. Meng, L. Nellissen, L. Grosenick, T.A. Milner, K.Deisseroth, H. Bito, H. Kasai, C. Liston. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. 2019 Apr 12; Vol 364, Issue 6436. DOI: 10.1126/science.aat8078.
Highlights:
- Antidepressant-dose ketamine selectively restores lost spines.
- Ketamine rescures PFC (pre-frontal cortex) microcircuit dysfunction.
- Prefrontal spinogenesis sustains the remission of depression-related behavior over time.
- 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.
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 keta-mine 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.
