GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine

Abstract

A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior.DOI: http://dx.doi.org/10.7554/eLife.03581.001

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

“…For example, deletion of GluN2B in principal cortical neurons mimics and occludes the actions of ketamine on behavior, glutamatergic synaptic transmission and protein synthesis. 86 Knockdown of GluN2B in the bed nucleus of the stria terminalis also mimics the affective effect of ketamine 87 and deletion of GluA1 in glutamatergic neurons during adolescence induces behavioral alterations that resemble schizophrenia-like abnormalities but not depression-or anxiety-like alterations. 88,89 Knock-in mice in which Ser 845 -GluA1 is replaced by alanine demonstrate loss of ketamineinduced synaptic potentiation in the hippocampus and impaired behavioral improvement induced by ketamine.…”

“…94 Ketamine was shown to increase BDNF in the hippocampus but this effect was not sustained after 24 h. 20 Our results do not allow us to determine if ketamine alters the levels of BDNF in the NAc and VTA, because the levels of this growth factor were unaltered 24 h after the injection, which might indicate that BDNF levels have already returned to baseline levels both in the NAc and VTA. Enhanced AMPAR function, as demonstrated by, for example, enhanced AMPA/NMDA ratio, increased glutamatergic synaptic transmission or increased phosphorylation of GluA1, 5,7,38,86,95 was suggested to mediate synaptic plasticity underlying the antidepressant effects of ketamine and (2R,6R)-HNK. These observations were made in the hippocampus or prefrontal cortex.…”

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

“…In addition to its role as an adaptor protein, it has been shown that Homer functions as ligand and directly modulates the Ca 2+ release gain via ryanodine receptor (Feng et al, 2002). The long Homer1b/c links metabotropic glutamate receptors (mGluR1 and mGluR5) with NMDA receptors (Perroy et al, 2008;Bertaso et al, 2010) and many proteins involved in Ca 2+ signaling Feng et al, 2002;Hwang et al, 2003;Yuan et al, 2003), all of which have been implicated in the pathophysiology of mood disorders (Galeotti et al, 2008a,b;Krystal et al, 2010;Miller et al, 2014;Newell and Matosin, 2014). Therefore, abnormal clustering and declustering of Homer1b/c may provide an important mechanism that underlies the pathophysiological processes of depression (Szumlinski et al, 2006;Luo et al, 2012).…”

“…However, how Homer1a mediates antidepressant effects is currently unknown. As the key scaffolding molecule at the PSD, constitutively expressed long Homers form a polymeric network complexes linking mGluR5 with NMDA receptors and various proteins involved in Ca 2+ homeostasis Feng et al, 2002;Hwang et al, 2003;Yuan et al, 2003;Perroy et al, 2008;Bertaso et al, 2010), which have been all implicated in the pathophysiology and treatment of depression (Galeotti et al, 2008a,b;Krystal et al, 2010;Miller et al, 2014;Newell and Matosin, 2014). The induction of Homer1a, which acts as a dominant negative protein and declusters long Homer complexes, might serve as a therapeutic method in depression to modulate activity of the target proteins.…”

Coadministration of ketamine with conventional antidepressants in animal models of depression

“…The summary of pharmacodynamics is (1) blockade of interneuronal NMDA receptors, (2) disinhibition of pyramidal cells leading to a glutamate surge, (3) activation of the AMPA receptors, (4) blockade of the excitotoxic extrasynaptic NMDA receptors, (5) activation of synaptogenic intracellular signaling and brain-derived neurotropic factor pathways, and (6) stimulation of the mammalian target of rapamycin. [17][18][19][20][21] In another study, Salat et al studied the antidepressant effect of ketamine, norketamine and dehydro ketamine using the forced swim test. They concluded that ketamine (10 mg/kg) and norketamine (50 mg/kg) reduced immobility time whereas dehydro norketamine did not.…”