TIP60 buffers acute stress response and depressive behaviour by controlling PPARγ-mediated transcription.

Tat-interacting protein 60 (TIP60) as nuclear receptors (NRs) coregulator, acts as a tumor suppressor and also has promising therapeutic potential to target Alzheimer's disease. Stress has been implicated in many psychiatric disorders, and these disorders are characterized by impairments in cognitive function. Until now, there are no experimental data available on the regulatory effect of TIP60 in acute stress and depression. There is also no definitive explanation on which specific modulation of target gene expression is achieved by TIP60. Here, we identify TIP60 as a novel positive regulator in response to acute restraint stress (ARS) and a potentially effective target of antidepressants. Firstly, we discovered increased hippocampal TIP60 expressions in the ARS model. Furthermore, using the TIP60 inhibitor, MG149, we proved that TIP60 function correlates with behavioral and synaptic activation in the two-hour ARS. Secondly, the lentivirus vector (LV)-TIP60overexpression (OE) was injected into the hippocampus prior to the chronic restraint stress (CRS) experiments and it was found that over-expressed TIP60 compensates for TIP60 decrease and improves depression index in CRS. Thirdly, through the intervention of TIP60 expression in vitro, we established the genetic regulation of TIP60 on synaptic proteins, confirmed the TIP60 function as a specific coactivator for PPARγ and found that the PPARγ-mediated TIP60 function modulates transcriptional activation of synaptic proteins. Finally, the LV-TIP60OE and PPARγ antagonist, GW9662, were both administered in the CRS model and the data indicated that blocking PPARγ significantly weakened the protective effect of TIP60 against the CRS-induced depression. Conclusively, these findings together support TIP60 as a novel positive factor in response to acute stress and interacts with PPARγ to modulate the pathological mechanism of CRS-induced depression.

Two-hour acute restraint stress facilitates escape behavior and learning outcomes through the activation of the Cdk5/GR P S211 pathway in male mice.

Acute stress exerts pleiotropic actions on learning behaviors. The induced negative effects are sometimes adopted to measure the efficacy of particular drugs. Until now, there are no detailed experimental data on the time-gradient effects of acute stress. Here, we developed the time gradient acute restraint stress (ARS) model to precisely assess the roles of different restrain times on inducing acute stress. Time gradient ARS facilitates escape behaviors and learning outcomes, peaking at 2 h-ARS and then declining to baseline at 3.5 h-ARS as confirmed by time gradient post-stress data. Furthermore, time gradient ARS activates glucocorticoid receptor (GR) phosphorylation site at Serine211 (P S221) as an inverted V-shaped pattern peaking at 2 h-ARS, whereas that of the GR phosphorylation site at Serine226 (P S226) from 2 h-ARS to 3.5 h-ARS. The 2 h-ARS but not 3.5 h-ARS enhances synaptic plasticity and genes transcription associated with learning and memory in the hippocampus of male mice. The Cdk5 inhibitor, roscovitine, blocks this facilitation effect by intervening in GR phosphorylation at Serine211 in the 2 h-ARS mice. Altogether, these findings show that the time gradient ARS selectively activates GR phospho-isoforms and differentially influences the behaviors along with maintaining a relationship between 2 h-ARS and Cdk5/GR P S211-mediated transcriptional activity.

Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription.

Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully understood. Voltage-gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD-related abnormal neuronal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we have shown that the reduction of VGSC α-subunit Nav1.6 (by injecting adeno-associated virus (AAV) with short hairpin RNA (shRNA) into the hippocampus) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 transgenic mice. Concurrently, amyloid plaques in the hippocampus and levels of soluble Aß are significantly reduced. Interfering with Nav1.6 reduces the transcription level of ß-site APP-cleaving enzyme 1 (BACE1), which is Aß-dependent. In the presence of Aß oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium-calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aß in APP/PS1 transgenic mice, alleviates synaptic loss, improves learning and memory disorders in APP/PS1 mice after downregulating Nav1.6 in the hippocampus. Our study offers a new potential therapeutic strategy to counteract hippocampal hyperexcitability and subsequently rescue cognitive deficits in AD by selective blockade of Nav1.6 overexpression and/or hyperactivity.