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. Author manuscript; available in PMC: 2017 Dec 1.
Published in final edited form as: Neuropharmacology. 2016 Sep 12;111:242–252. doi: 10.1016/j.neuropharm.2016.09.011

Figure 8. Schematic of the molecular mechanisms underlying rapid-acting antidepressants.

Figure 8

Rapid-acting antidepressants, including ketamine, LY341495, and GLYX-13 increase phospho-ERK and BDNF release via an activity dependent mechanism. This could occur via inhibition of NMDA receptors on tonic firing GABAergic neurons resulting in disinhibition of glutamatergic activity and a burst of extracellular glutamate. LY341495 blocks mGlur2/3 receptors that can be located on glutamate presynaptic terminals and regulate glutamate release. Increased release of glutamate leads to activation of AMPA receptors and depolarization of postsynaptic neurons resulting in activation of voltage dependent calcium channels (VDCCs) and subsequent BDNF release and TrkB receptor activation. TrkB receptors stimulate ERK and the mTORC1 signaling pathway, including pS6K resulting in increased translation of synaptic proteins, such as GluR1 and PSD95 required for synaptogenesis. The activity dependent action of these agents was confirmed in the current study by demonstrating that the neuronal silencing agent muscimol and the AMPA antagonist NBQX block the increase in phospho-ERK and BDNF release. A role for BDNF-TrkB signaling was demonstrated by blockade with the TrkB antagonist K252a.