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Ketamine helps neurons regrow lost connections

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The Role of Prefrontal Cortical Spine Formation in Sustaining the Antidepressant Effects of Ketamine

Depression is a common form of mental illness, and the mechanisms that drive the induction, remission, and recurrence of depressive episodes are not well understood. Ketamine, an antidepressant medication, has been shown to relieve depressive symptoms rapidly, making it an opportunity to study the mechanisms involved in transitions from depression to remission and test whether the mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

A recent study used two-photon imaging to investigate the impact of chronic stress and ketamine on dendritic spine remodeling and neuronal activity dynamics in the prefrontal cortex (PFC). Chronic stress was found to cause depression-related behavior and a loss of correlated multicellular ensemble activity in PFC projection neurons. Specifically, chronic stress caused the elimination of postsynaptic dendritic spines in targeted, branch-specific regions of prefrontal cortical pyramidal cells.

Antidepressant-dose ketamine was found to selectively rescue eliminated spines and restore coordinated activity in multicellular ensembles, which predicted motivated escape behavior. Interestingly, 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, a photoactivatable probe was used to selectively reverse the effects of ketamine on spine formation in the PFC. The results showed that newly formed spines play a necessary and specific role in sustaining ketamine's antidepressant effects on motivated escape behavior. However, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

The study suggests that 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. The findings also suggest that pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may be useful for promoting sustained remission.

In conclusion, depression is an episodic form of mental illness, and the mechanisms underlying its induction and remission are not well understood. Ketamine has been shown to be an effective antidepressant medication, and recent research has shed light on how it works at the neuronal level. By rescuing lost spines and restoring coordinated ensemble activity in PFC microcircuits, ketamine has been found to sustain remission of specific depression-related behaviors. The study's findings have important implications for the development of new treatments for depression that can be used to promote sustained remission.

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