Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects

Abstract

Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1–NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.

( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions

“…To clarify whether ketamine's action to prevent mGlu 2/3 receptor agonist-induced hyperthermia is due to NMDAR inhibition, we assessed three distinct NMDAR antagonists: (i) (+)-MK-801, a noncompetitive NMDAR antagonist, which acts at the same phencyclidine (PCP)/ketamine site of the NMDAR; (ii) (±)-CPP, a competitive NMDAR antagonist; and (iii) Ro 25-6981, a GluN2B-specific NMDAR antagonist; we used doses known to exert putative antidepressant-relevant actions in rodents (15,33,(72)(73)(74)(75)(76) and to induce NMDAR inhibition-mediated behaviors (75,(77)(78)(79). Administration of these NMDAR antagonists did not prevent mGlu 2/3 receptor agonist-induced hyperthermia ( Fig.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…In particular, a single administration of the GluN2B acting NMDAR antagonist Ro 25–6981 decreases behavioral despair in the 24-hr forced-swim test [42, 47, 93, 94], novelty-suppressed feeding test [42, 47, 55], novelty-induced hypophagia [56] and reverses anhedonia following chronic mild stress [55]. Similarly, ifenprodil, another GluN2B-NMDAR antagonist, reverses chronic unpredictable stress-induced sucrose preference deficits and behavioral despair in rodents following a single administration [95]. Recently, it has been shown that ketamine might induce its acute (1-h) antidepressant actions via blockade of NMDAR-dependent burst activity in the lateral habenula neurons [96]; however, it remains to be determined whether this action of ketamine is responsible for the long-lasting antidepressant actions of the drug.…”

“…Finally, sub-chronic (5 days) administration of a 5-HT 2C antagonist [239], as well as partial activation of the GABA A receptor (via inhibition of GLO1) [179], increase BDNF protein levels in the mPFC and/or hippocampus of mice. In addition, administration of ketamine, GluN2-NMDAR antagonists, mGluR 2/3 antagonists and electroconvulsive shock reverse chronic stress-induced reduction in BDNF levels in the PFC [95, 198] and hippocampus [198, 310–312] of rodents, suggesting that BDNF induction could be considered as a marker of rapid antidepressant efficacy. Short-term (6–48 h) sleep deprivation has been shown to both increase [303, 313] or decrease [314, 315] hippocampal BDNF levels in stress-naïve rats, and has been shown to restore decreased BDNF levels in the hippocampus following chronic stress [316].…”

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

“…In 2009, a novel and selective DAPK family inhibitors were identified based on oxazol‐5‐one core by structural based virtual screening . Representative examples are shown in Figure .…”