STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17

Abstract

Background In tauopathies, the degree of neurodegeneration and memory impairment positively strongly correlates with the amount of abnormal tau aggregates. Recently, we found that human wild-type tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of genes coding for synaptic N-methyl-D-aspartate receptors (NMDARs). STAT3 has similar specific DNA binding element GAS as STAT1, however, the role of STAT3 in cognitive deficits induced by tau accumulation has not reported until now.Methods The activity of the transcription factor was analyzed by luciferase reporter assay or electrophoresis mobility shift assay. AAV virus (AAV-Cre, AAV-P301L, AAV-STAT3 or AAV-K410/3R-STAT1) was infused stereotaxically into the hippocampal CA3 regions of STAT3flox/flox or C57 mice. The spatial learning and memory of the animals were assessed by Morris water maze, the contextual fear conditioning and new object recognition test. The synaptic plasticity was measured by electrophysiological recording and the spine density was detected by Golgi staining. RT-PCR and Western blotting were used to detect the mRNA and protein levels.Results We found that P301L-hTau accumulation acetylated STAT1 at lysine 410 and 413 sites to bind with STAT3 in the cytoplasm which inhibited the nuclear translocation and inactivated STAT3, though phosphorylation of STAT3 at Tyr705, which leads to STAT3 nuclear translocation and DNA binding, increased. Knockdown of STAT3 by AAV-Cre in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression, synaptic and memory impairments. Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression. Further study revealed that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDAR1, NMDAR2A and NMDAR2B promoters.Conclusion These findings indicate that accumulated P301L-hTau impairs synaptic plasticity by inactivating STAT3 to suppress NMDARs expression, thereby revealing a novel mechanism for P301L-hTau-associated synapse and cognition deficits.