Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation

A single dose of NV-5138, a small molecule that modulates sestrin and crosses the blood-brain barrier, produced rapid and long-lasting antidepressant effects and quickly reversed anhedonia caused by chronic stress in mice. These effects required BDNF release in the medial prefrontal cortex, as blocking BDNF with an antibody or using a BDNF polymorphism that prevents activity-dependent release eliminated the behavioral responses. NV-5138 also rapidly increased synapse number and function in the medial prefrontal cortex and reversed synaptic deficits from chronic stress. The findings indicate that pharmacologically modulating sestrin activates mTORC1 signaling and BDNF release, offering a new approach for rapid-acting antidepressants.

Study at a glance

Abstract

Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.