Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aß oligomer-induced long-term synaptic plasticity and memory impairment.

Expression of CREB-regulated transcription coactivator 1 (CRTC1) in the hippocampus is impaired in Alzheimer's disease (AD). However, CRTC1 related mechanisms associated with long-term synaptic plasticity impairment and cognitive decline in the onset of AD are unknown. In this study, electrophysiological recordings indicated that lentivirus-mediated CRTC1 overexpression effectively ameliorates suppression of late-phase long-term potentiation (L-LTP) in rat hippocampal slices treated with oligomeric amyloid ß(1-42) peptides (oAß42) (200 nM). In addition, application of oAß42 and genetic knockdown of CRTC1 by lentivirus-mediated CRTC1-shRNA inhibit L-LTP, whereas their combination does not further impair L-LTP. Brain-derived neurotrophic factor (BDNF), an important downstream protein confers protection of CRTC1 overexpression against oAß42-induced L-LTP impairment as shown by administration of K252a (200 nM) and TrkB-FC (20 µg/ml). Furthermore, behavioral and western blotting analyses showed that CRTC1 overexpression reverses oAß42-induced hippocampal-dependent cognitive deficits, downregulation of CRTC1 and BDNF expression. Notably, CRTC1-shRNA directly elicits cognitive deficits. In summary, these findings show that hippocampal CRTC1 signaling is affected by soluble oAß, and CRTC1-BDNF pathway is involved in hippocampal L-LTP impairment and memory deficits induced by oAß42.

CREB-regulated transcription coactivator 1: important roles in neurodegenerative disorders.

The cAMP-responsive element binding protein (CREB)-regulated transcription coactivator, CRTC (also known as transducer of regulated CREB, TORC), is identified as a potent modulator of cAMP response element (CRE)-driven gene transcription. The CRTC family consists of three members (CRTC1-3), among which the CRTC1 shows the highest expression in the brain. Several studies have demonstrated that the CRTC1 plays critical roles in neuronal dendritic growth, long-term synaptic plasticity, memory consolidation and reconsolidation etc., whereas dysfunction of CRTC1 is mainly involved in neurodegenerative disorders. In light of these findings, we aim to review recent research reports that indicate the CRTC1 dysfunction and its underlying mechanisms in the neurodegenerative disorders.

PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13.

BACKGROUND: VGF (nonacryonimic) and phosphatidylinositol 3-kinase (PI3K)/AKT (also known as protein kinase B, PKB)/mammalian target of rapamycin (mTOR) signaling play pivotal roles in depression. However, whether phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF participates in rapid-acting antidepressant-like actions of GLYX-13 is unclear. METHODS: Herein, we evaluated the effects of acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) in the forced swim test. In addition, we assessed whether the acute treatment with GLYX-13 reverses the depressive-like behaviors induced by chronic unpredictable mild stress. Furthermore, we determined whether the Vgf knockdown in hippocampus of mice blocks the effects of GLYX-13. Moreover, we also demonstrated the effects of intra-hippocampus infusion of LY294002 (10 nmol/side), a specific phosphatidylinositol 3-kinase inhibitor prior to the treatment of GLYX-13 in the forced swim test. Lastly, whether alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mTOR activation involves in the antidepressant-like effects of GLYX-13 was examined. RESULTS: Our results shown that GLYX-13 dose-dependently reversed the depressive-like behaviors in forced swim test. Additionally, GLYX-13 significantly reversed the downregulation of phosphorylation of AKT, mTOR, and eukaryotic elongation factor 2 as well as VGF induced by chronic unpredictable mild stress in hippocampus. Further, Vgf knockdown in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Moreover, intra-hippocampus infusion of LY294002 significantly abolished the antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Finally, antidepressant-like effects of GLYX-13 required AMPA receptor and mTOR activation, as evidenced by the ability of NBQX and rapamycin to block the effects of GLYX-13, respectively. CONCLUSIONS: Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13.

The preventive effect of NR2B and NR2D-containing NMDAR antagonists on Aß-induced LTP disruption in the dentate gyrus of rats.

Amyloid ß-protein (Aß) in the brain of Alzheimer's disease (AD) potently inhibits the synaptic plasticity subsequently causing the cognitive deficits. Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. Different NR2 subunits are involved in NMDA receptor-dependent LTP. In the present study, we investigated the roles of NR2B and NR2D-containing NMDAR on Aß(1-42)-induced LTP deficits in the hippocampal slices of rats by using selective NMDAR antagonists. First, we found that Aß(1-42) significantly inhibited the LTP in the dentate gyrus of slices as reported before. Following that the Aß(1-42)-induced LTP inhibition was prevented by the pre-perfusion of the specific NR2B-containing NMDAR antagonists ifenprodil (approximately >200-fold selectivity for NR2B) and Ro25-6981 (>3,000-fold selectivity for NR2B), as well as PPDA, a specific NR2D receptor antagonist. Meanwhile, the antagonists on their own had no or only partial effects on the normal LTP in the same dose condition. These findings not only support the effects of NR2B and NR2D subunits on Aß(1-42)-induced LTP deficits, but also imply that preferentially targeting NR2B- and NR2D-containing NMDARs may provide an effective means to prevent cognitive deficits in the early AD.