BDNF Release Is Required for the Behavioral Actions of Ketamine

Ketamine's rapid antidepressant effects depend on the release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC), which is triggered by activation of L-type voltage-dependent calcium channels (VDCCs). Infusing a neutralizing BDNF antibody into the mPFC blocked ketamine's behavioral effects in the forced swim test. Pretreatment with either nifedipine or verapamil, two different L-type calcium channel antagonists, also blocked these effects. In primary cortical neurons, ketamine stimulated BDNF release, and this release was prevented by inhibiting AMPA receptors or L-type VDCCs. The findings indicate that L-type VDCC activation and BDNF release mediate ketamine's antidepressant actions.

Study at a glance

Abstract

BACKGROUND: Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC). METHODS: Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine. RESULTS: The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs. CONCLUSIONS: Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.