Yuan-Jian Yang

Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function

Deficits in learning and memory accompanied by age‐related neurodegenerative diseases are closely related to the impairment of synaptic plasticity. In this study, we investigated the role of thiol redox status in the modulation of the N‐methyl‐d‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP) in CA1 areas of hippocampal slices. Our results demonstrated that the impaired LTP induced by aging could be reversed by acute administration of reductants that can regulate thiol redox status directly, such as dithiothreitol or β‐mercaptoethanol, but not by classical anti‐oxidants such as vitamin C or trolox. This repair was mediated by the recruitment of aging‐related deficits in NMDAR function induced by these reductants and was mimicked by glutathione, which can restore the age‐associated alterations in endogenous thiol redox status. Moreover, antioxidant prevented but failed to reverse H2O2‐induced impairment of NMDAR‐mediated synaptic plasticity. These results indicate that the restoring of thiol redox status may be a more effective strategy than the scavenging of oxidants in the treatment of pre‐existing oxidative injury in learning and memory.

Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels

BACKGROUND AND PURPOSE Sinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen‐glucose deprivation‐reperfusion (OGD‐R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism.

The flavonoid baicalein promotes NMDA receptor-dependent long-term potentiation and enhances memory.

BACKGROUND AND PURPOSE There is growing interest in the physiological functions of flavonoids, especially in their effects on cognitive function and on neurodegenerative diseases. The aim of the current investigation was to evaluate the role of the flavonoid baicalein in long‐term potentiation (LTP) in the hippocampal CA1 region and cognitive behavioural performance.

Orexin-A Activates Hypothalamic AMP-Activated Protein Kinase Signaling through a Ca2+-Dependent Mechanism Involving Voltage-Gated L-Type Calcium Channel

Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca2+ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor–phospholipase C–protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A’s orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A–induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-β-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca2+-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.

Phosphatidylinositol-linked novel D1 dopamine receptor facilitates long-term depression in rat hippocampal CA1 synapses

Recent work has demonstrated that a phosphatidylinositol (PI)-linked D(1) dopamine receptor selective agonist, SKF83959, mediates phosphatidylinositol hydrolysis via activation of phospholipase C(beta) in brain. Specific contributions of SKF83959 to synaptic plasticity have not been well elucidated. The aim of the current investigation was to characterize the role of SKF83959 on long-term depression (LTD) in the CA1 region of rat hippocampal slices and to explore the molecular events leading to these changes. The results indicated that SKF83959 stimulation significantly depressed field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner and facilitated the induction of LTD by LFS. SKF83959-facilitated LTD required activation of phospholipase C (PLC). NMDA receptors were involved in this response. Calcium chelator, BAPTA-AM prevented SKF83959-facilitated LTD, indicating that cytosolic free calcium concentration ([Ca(2+)](i)) elevation could account for this response. Furthermore, SKF83959-facilitated LTD was significantly depressed in the presence of calcineurin (PP2B) inhibitors cyclosporin A (CsA) and associated with a persistent increase in the expression of calcineurin A. Taken together, these findings demonstrate a novel role for PI-linked D(1) dopamine receptor in the neuromodulation of hippocampal LTD.

Regulation of emotional memory by hydrogen sulfide: role of GluN2B-containing NMDA receptor in the amygdala

As an endogenous gaseous molecule, hydrogen sulfide (H2S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2S on amygdala‐mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2S could regulate emotional memory. It was shown that the H2S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2S markedly enhanced amygdala‐dependent cued fear memory in rats. Moreover, it was found that H2S selectively increased the surface expression and currents of NMDA‐type glutamate receptor subunit 2B (GluN2B)‐containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B‐containing NMDARs in lateral amygdala eliminated the effects of H2S to enhance amygdalar long‐term potentiation and cued fear memory. These results demonstrate that H2S can regulate amygdala‐dependent emotional memory by promoting the function of GluN2B‐containing NMDARs in amygdala, suggesting that H2S‐associated signaling may hold potential as a new target for the treatment of emotional disorders.

Interactions between N-Ethylmaleimide-Sensitive Factor and GluR2 in the Nucleus Accumbens Contribute to the Expression of Locomotor Sensitization to Cocaine

Many studies have reported a withdrawal-dependent increase in synaptic AMPA receptor (AMPAR) levels in the nucleus accumbens (NAc) of cocaine-sensitized rats; however, the exact relationship between the expression of sensitization and altered AMPAR surface expression in the NAc has not yet been investigated. We demonstrated that the expression of behavioral sensitization was negatively controlled by N-ethylmaleimide-sensitive factor (NSF)-GluR2 interactions in the NAc. The upregulation of NSF–GluR2 interactions, which may be resulted by the increase in NSF S-nitrosylation after withdrawal from cocaine, was associated with the changes in the expression of behavioral sensitization. Disruption of NSF–GluR2 interactions in the NAc with a specific peptide, TAT-pep-R845A, increased the locomotor response of rats to cocaine by decreasing GluR2 surface insertion. In contrast, prevention of GluR2-containing AMPARs removal from synapses with Pep2-EVKI attenuated the expression of behavioral sensitization. Similarly, treatment with the nitric oxide donor, S-Nitroso-N-acetyl-DL-penicillamine (SNAP), attenuated the expression of locomotor sensitization by promoting GluR2 surface expression. This effect was mediated by the binding of S-nitrosylated NSF to GluR2, which promoted the surface expression of AMPARs. Noticeably, exogenous injection of SNAP into NAc also attenuated the expression of cocaine-induced conditioned place preference. Thus, these results indicate that increased NSF–GluR2 interactions in the NAc after withdrawal from cocaine attenuated the expression of behavioral sensitization and serves as a negative regulatory mechanism in drug-exposed individuals.

Aging-related alterations in the expression and distribution of GluR2 and PICK1 in the rat hippocampus

Deficit in synaptic plasticity in the hippocampus frequently occurs during normal aging. Although the protein level and calcium permeability of AMPARs alter with aging, the alteration of AMPARs and their regulatory proteins during aging are far from understanding. Dynamics of GluR2 subunit are dependent on the function of protein interacting with Cα kinase 1 (PICK1), PKCα and calcineurin (CaN). Here, we firstly show that the expression of PICK1 and CaN B decreased significantly in the hippocampus of old rats compared to that of young and adult rats. The decrease was accompanied by a reduction of GluR2 and PKCα and an increase in CaN A. Next, we found that in young and adult rats, the distribution of PICK1 and GluR2 diffused in the cytoplasm of hippocampal neurons, but closely around perinuclear in the hippocampal neurons of old rats. These results suggest that the expression of GluR2, PICK1, PKCα and CaN B significant decreased in the hippocampus and these alterations may lead to altered distribution of GluR2 and PICK1 during aging.