Figure 5
From: Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects
Inhibition of GluN2B–DAPK1 interaction produced rapid and sustained antidepressant-like effects. (a) Timeline of surgery, CUS exposure, drug microinjection and behavioral testing (n=10–15 per group). (b, c) Tat-GluN2BCT rapidly increased sucrose preference in the SPT (b) and decreased immobility time in the FST (c) in CUS rats. (d) Representative GluN2B immunoprecipitation after Tat-GluN2BCT and Tat-sGluN2BCT treatment. Administration of Tat-GluN2BCT led to the dissociation of GluN2B–DAPK1 complexes (n=8 per group). (e) Timeline of surgery, CUS exposure, drug microinjection and behavioral testing 7 days later (n=10–13 per group). (f, g) Tat-GluN2BCT reversed the decrease in sucrose preference in the SPT (f) and the increase in immobility time in the FST (g) induced by CUS 7 days after administration. **P<0.01, compared with control+Tat-sGluN2BCT group; ##P<0.01, compared with CUS+Tat-sGluN2BCT group. (h) Schematic diagram that illustrates the involvement of GluN2B-containing NMDARs and associated signaling molecules in the mPFC in depressive-like behavior. Chronic unpredictable stress exposure or the blockade of glutamate transporter-1 (GLT-1) impaired glutamate uptake into astrocytes, thus causing extracellular glutamate to accumulate and overflow onto extrasynaptic GluN2B-containing NMDARs. DAPK1 was activated when extracellular glutamate accumulated and phosphorylated GluN2B at Ser1303, leading to calcium influx. The activation of GluN2B by DAPK1 decreased p-CREB and BNDF levels and subsequently induced synaptic protein deficits and depressive-like behavior. Selective GluN2B antagonism, DAPK1 inhibition or uncoupling DAPK1 from the NMDAR GluN2B subunit rapidly rescued depressive-like behavior, followed by the normalization of GluN2B activation and increases in p-CREB and BDNF levels. GluN2B antagonism reversed the synaptic protein deficits that were caused by CUS exposure. BDNF, brain-derived neurotrophic factor; CREB, cyclic AMP response element-binding protein; CUS, chronic unpredictable stress; DAPK1, death-associated protein kinase 1; FST, forced swim test; mPFC, medial prefrontal cortex; NMDAR, N-methyl-D-aspartate receptor; SPT, sucrose preference test.
