Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade
Elena Enosyreva, Anita E Autry, Ege Ekavalali, Lisa M Monteggia
Frontiers in Molecular Neuroscience September 11, 2015 Peer reviewed DOI: 10.3389/fnmol.2014.00094 via DOAJ
Summary
Ketamine does not produce an antidepressant response or synaptic potentiation in juvenile animals, as shown by tests like the novelty suppressed feeding and forced swim test. In contrast, older animals (6-9 weeks old) respond differently, indicating that developmental factors influence ketamine's antidepressant effects. Additionally, the NMDA receptor antagonist AP5 can induce synaptic potentiation in mature hippocampal tissue, suggesting that NMDA receptor blockade is necessary for ketamine's efficacy.
Study at a glance
| Population | juvenile animals |
|---|---|
| Key finding | Ketamine did not produce an antidepressant response or trigger synaptic potentiation in juvenile animals. |
Abstract
Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old). The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.