NMDA receptor-dependent long-term depression in the lateral habenula: implications in physiology and depression

Miseon Kang,Jihyun Noh,Jun-Mo Chung

doi:10.1038/s41598-020-74496-w

Abstract

Abnormally increased neuronal activity in the lateral habenula (LHb) is closely associated with depressive-like behavior. Despite the emphasis on the pathological importance of NMDA receptor (NMDAR)-dependent long-term depression (LTD) and the involvement of calcium permeable AMPA receptor (CP-AMPAR) as major Ca2+ source, the functions of NMDAR and CP-AMPAR on LTD modulation in the LHb still have not been fully investigated. Here, we found that NMDAR-dependent LTD by low frequency stimulation was induced in both synaptic and extrasynaptic regions in the LHb. In addition, CP-AMPAR was necessary for the activation of NMDAR in the induction phase of NMDAR-dependent LTD. The acute stress, which induced depressive behavior, had a blocked effect on synaptic NMDAR-dependent LTD but left extrasynaptic NMDAR-dependent LTD intact. These findings show that NMDAR-dependent LTD in LHb plays an important role in regulating neuronal activity, which is probable to be excessively increased by repeated stress, via maintaining homeostasis in both synaptic and extrasynaptic regions of the LHb. Moreover, NMDAR and CP-AMPAR may serve as a depression-related modulator and be regarded as a promising therapeutic target for treatment of psychopathology such as depression.

Highlights

Increased neuronal activity in the lateral habenula (LHb) is closely associated with depressive-like behavior
To determine which glutamate receptors are mainly involved in the long-term modulation of excitatory transmission in the LHb, we examined the effect of various glutamate receptor antagonists on Lowfrequency stimulation (LFS)-induced long-term depression (LTD) (Fig. 1)
All these results clearly show that the activation of GluN2A- or GluN2B- containing NMDA receptor (NMDAR) leads to LTD induction triggered by LFS in LHb

Summary

Introduction

Increased neuronal activity in the lateral habenula (LHb) is closely associated with depressive-like behavior. The mGluR-dependent LTD modulated the excitatory and inhibitory output signaling, and it engaged in modulating the neuronal activity in the LHb. calcium-permeable AMPA receptor (CP-AMPAR), considered to be a C a2+ source, is involved in changing LTD to long-term potentiation (LTP) in the LHb neuron[1,4], a molecular mechanism concerning the fundamental modulation of LTD has not been fully reported. A recent study reported that depressive-like behavior caused by repetitive stress is associated with an increase of bursting firing in the LHb, and inhibition of NMDAR by ketamine leads to an antidepressant effect[17]. In this report, ketamine has shown antidepressant effects by inhibiting NMDAR-dependent bursting, and there is still no research on the association between NMDA-dependent LTD in LHb and depressive behavior. We need to predict the functional role of NMDAR by examining the effect of NMDAR-dependent LTD on the LHb in the depression model

Methods

Results

Conclusion