Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
Taro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, Ronald S. Duman
Taro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, Ronald S. Duman
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Research Article Neuroscience

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

Abstract

Preclinical studies demonstrate that rapid-acting antidepressants, including ketamine, require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity and endocrine and metabolic signals, notably including 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 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 brain-derived neurotrophic factor (BDNF) release, as the behavioral responses were blocked by infusion of a BDNF-neutralizing Ab into the medial prefrontal cortex (mPFC) or, in mice, with a knockin of a BDNF polymorphism that blocked 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 produces rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin may be an attractive approach for the development of rapid-acting antidepressants.

Authors

Taro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, Ronald S. Duman

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Figure 6

Influence of NV-5138 on spine number and function and synaptic proteins in the PFC.

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Influence of NV-5138 on spine number and function and synaptic proteins ...
(A) Representative traces showing postsynaptic currents recorded from layer V pyramidal neurons in mPFC brain slices from vehicle- or NV5138-treated rats (24 hours after drug treatment). (B) Summary of data showing that frequencies of 5-HT– (20 μM) and hypocretin-induced (200 nM) EPSCs are increased by NV-5138; n = 35 cells/8 rats for control; n = 30 cells/8 rats for NV-5138. *P < 0.05; ** P < 0.01, t test. Absolute values for baseline EPSC frequency is 3.58 ± 0.4 (Hz); n = 35 cells/8 rats for control and 2.63 ± 0.48 (Hz); n = 30 cells/8 rats for NV-1538 (C). Representative images of high-magnification Z-stack projections of apical dendritic segments from slices collected 24 hours following vehicle or NV-5138 administration. Scale bar: 5 μm. (D) NV-5138 increased overall spine density (t = 2.72, P = 0.015) due to increases in densities of thin (t = 2.20, P = 0.04) and mushroom spines (t = 2.01, P = 0.05). n = 9 cells/8 rats for control and 9 cells/5 rats for NV-5138. (E–G) Rats were administered vehicle, ketamine (10 mg/kg), or NV-5138 (160 mg/kg), and PFC dissections were collected 24 hours later. Levels of the postsynaptic proteins including (E) GluR1, (F) PSD95, (G) synapsin1, and (H) SV2A were determined by Western blot analysis. GAPDH levels were also determined to control for loading differences. n = 6/group. *P ≤ 0.05; **P < 0.01 Student’s t test.