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Mechanisms of Ketamine's Sustained Antidepressant Effect

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Depression is characterized by a loss of synaptic connections in regions of the brain involved in emotional regulation and cognitive function, and antidepressant treatments generally result in a compensatory increase in the number of these connections. Previous studies have shown that a single sub-anesthetic dose of ketamine, a rapid-acting antidepressant, increases synaptic connectivity in excitatory neurons projecting from the prefrontal cortex to other brain regions involved in cognitive regulation and function, countering the destabilization and loss of synapses observed in depression. However, there is little understanding of the molecular pathways and mechanisms involved in synapse restoration at the synapse structure level. Due to the role of proteins involved in synapse formation and maintenance, we sought to determine whether ketamine’s antidepressant mechanism is dependent on these proteins in projecting neurons of excitatory circuits that contribute to emotional regulation. Mice were divided into groups with or without chronic stress and with conditional knockouts for the proteins of interest. They were then subjected to a series of behavioral tests and their brain tissue was analyzed for changes in excitatory synapse number. We found that ketamine’s promotion of synapse formation and sustained antidepressant-like effect on behavior was hindered in knockout mice. These findings revealed that ketamine is dependent on proteins involved in synapse formation and maintenance for its rescue of depressive-like behavior and restoration of excitatory synaptic connectivity.

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This item is under embargo until January 11, 2025.