Dataset Information

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

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.

SUBMITTER: Kang M

PROVIDER: S-EPMC7578045 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Kang Miseon M Noh Jihyun J Chung Jun-Mo JM

Scientific reports 20201021 1

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 Ca<sup>2+</sup> 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 sti ...[more]

PMID: 33087756

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Project description:UNLABELLED:Fragile X syndrome (FXS) is a neurodevelopmental disease. It is one of the leading monogenic causes of intellectual disability among boys with most also displaying autism spectrum disorder traits. Here we investigated the role of NMDA receptors on mGluR-dependent long-term depression (mGluR-LTD), a key biomarker in the disease, at four different developmental stages. First, we applied the mGluR agonist 3,5-dihydroxyphenylglycine in the absence or presence of the NMDAR blocker, APV, hereby unmasking the NMDAR component in this process. As expected, in the presence of APV, we found more LTD in the mouse KO than in WT. This, however, was only observed in the p30-60 age group. At all other age groups tested, mGluR-LTD was almost identical between KO and WT. Interestingly, at p60, in the absence of APV, no or very little LTD was found in KO that was completely restored by application of APV. This suggests that the underlying cause of the enhanced mGluR-LTD in KO (at p30) is caused by dysregulated NMDAR signaling. To investigate this further, we next used NMDAR-subunit-specific antagonists. Inhibition of GluN2B, but not GluN2A, blocked mGluR-LTD only in WT. This was in contrast in the KO where blocking GluN2B rescued mGluR-LTD, suggesting GluN2B-containing NMDARs in the KO are hyperactive. Thus, these findings suggest strong involvement of GluN2B-containing-NMDARs in the pathophysiology of FXS and highlight a potential path for treatment for the disease. SIGNIFICANCE STATEMENT:There is currently no cure for fragile X, although medications targeting specific FXS symptoms do exist. The FXS animal model, the Fmr1 knock-out mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD) leading to several clinical trials of mGluR5 inhibitors/modulators, yet all have failed. In addition, surprisingly little information exists about the possible role of other ion channels/receptors, including NMDA receptors (NMDAR), in mGluR-LTD. Here we focus on NMDARs and their regulation of mGluR-mediated LTD at different developmental stages using several different NMDAR blockers/antagonists. Our findings suggest dysregulated NMDARs in the pathophysiology of FXS leading to altered mGluR-mediated LTD. Together, these data will help to develop new drug candidates that could lead to reversal of the FXS phenotype.

Dataset Information

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

Publications

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

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