Figure 7. Mechanism for scopolamine to cause a burst of glutamate, activation of mTORC1 signaling, and increased synapse formation.

Scopolamine blockade of Ach-M1 receptors located on GABAergic interneurons results in disinhibition and a burst of glutamate transmission, activation of AMPA receptors, and depolarization of postsynaptic pyramidal neurons. This leads to activation of voltage dependent calcium channels (VDCC), which activates release of BDNF and the subsequent stimulation of TrkB receptors and the Akt-mTORC1 signaling pathway. This pathway controls the translation and synthesis of synaptic proteins, such as GluA1 and PSD95, that are required for the formation of new synapses that occur and are associated with the rapid antidepressant actions of scopolamine. Administration of rapamycin, a selective mTORC1 inhibitor, blocks the antidepressant actions scopolamine.