Zhuang-Li Hu

Antidepressant‐like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus

BACKGROUND AND PURPOSE Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients of Panax ginseng with little toxicity and has been shown to have neuroprotective effects. In this study, we investigated the antidepressant‐like effect of Rg1 in models of depression in mice.

Existence and distinction of acid-evoked currents in rat astrocytes.

Astrocytes are vital structures that support and/or protect neighboring neurons from pathology. Although it is generally accepted that glutamate receptors mediate most astrocyte effects, acid‐evoked currents have recently attracted attention for their role in this regard. Here, we identified the existence and characteristics of acid‐sensing ion channels (ASICs) and the transient receptor potential vanilloid type 1 (TRPV1) in astrocytes. There were two types of currents recorded under the application of acidic solution (pH 6.0) in cultured rat astrocytes. Transient currents were exhibited by 10% of the astrocytes, and sustained currents were exhibited by the other 90%, consistent with the features of ASIC and TRPV1 currents, respectively. Western blotting and immunofluorescence confirmed the expression of ASIC1, ASIC2a, ASIC3, and TRPV1 in cultured and in situ astrocytes. Unlike the ASICs expressed in neurons, which were mainly distributed in the cell membrane/cytoplasm, most of the ASICs in astrocytes were expressed in the nucleus. TRPV1 was more permeable to Na+ in cultured astrocytes, which differed from the typical neuronal TRPV1 that was mainly permeable to Ca2+. This study demonstrates that there are two kinds of acid‐evoked currents in rat astrocytes, which may provide a new understanding about the functions of ligand‐gated ion channels in astrocytes.

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression.

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.

Hyperoside protects cortical neurons from oxygen-glucose deprivation-reperfusion induced injury via nitric oxide signal pathway.

Hyperoside is a flavonoid compound and widely used in clinic to relieve pain and improve cardiovascular functions. However, the effects of hyperoside on ischemic neurons and the molecular mechanisms remain unclear. Here, we used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD-R) to investigate the protective effects of hyperoside on ischemic neuron injury and further explore the possible related mechanisms. Our results demonstrated that hyperoside protected cultured cortical neurons from OGD-R injury, it also relieved glutamate-induced neuronal injury and NMDA-induced [Ca(2+)](i) elevation. As for the mechanisms, hyperoside firstly attenuated the phosphorylation of CaMKII caused by OGD-R lesions. Meanwhile, hyperoside lessened iNOS expression induced by OGD-R via inhibition of NF-κB activation. Furthermore, ameliorating of ERK, JNK and Bcl-2 family-related apoptotic signaling pathways were also involved in the neuroprotection of hyperoside. Taken together, these studies revealed that hyperoside had protective effects on neuronal ischemia-reperfusion impairment, which was related to the regulation of nitric oxide signaling pathway.

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.

Chronic ceftriaxone treatment rescues hippocampal memory deficit in AQP4 knockout mice via activation of GLT-1.

Aquaporin-4 (AQP4) is the predominant water channel protein in the mammalian brain, and is mainly expressed in astrocytes. Besides its important role in water transport across the blood-brain barrier, our present study demonstrated that AQP4 deficiency impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent memory formation, accompanied by the increase in extracellular glutamate concentration and N-methyl-d-aspartate (NMDA) receptor-mediated currents in hippocampal dentate gyrus (DG) region. The impairment of LTP and memory formation of AQP4 knockout (KO) mice was mediated by the downregulation of glutamate transporter-1 (GLT-1) expression/function, since it can be rescued by β-lactam antibiotic ceftriaxone (Cef), a potent GLT-1 stimulator. These results suggest that AQP4 functions as the modulator of synaptic plasticity and memory, and chronic Cef treatment rescues hippocampal memory deficit induced by AQP4 knockout.

Disruption of PICK1 attenuates the function of ASICs and PKC regulation of ASICs

Acid-sensing ion channels (ASICs) extensively exist in both central and peripheral neuronal systems and contribute to many physiological and pathological processes. The protein that interacts with C kinase 1 (PICK1) was cloned as one of the proteins interacting with protein kinase C (PKC) and colocalized with ASIC1 and ASIC2. Here, we used PICK1 knockout (PICK1-KO) C57/BL6 mice together with the whole cell patch clamp, calcium imaging, RT-PCR, Western blot, and immunocytochemistry techniques to explore the possible change in ASICs and the regulatory effects of PKC on ASICs. The results showed that PICK1 played a key role in regulation of ASIC functions. In PICK1-KO mouse cortical neurons, both the amplitude of ASIC currents and elevation of [Ca(2+)](i) mediated by acid were decreased, which were attributable to the decreased expression of ASIC1a and ASIC2a proteins in the plasma membrane. PKC, a partner protein of PICK1, regulated ASIC functions via PICK1. The agonist and antagonist of PKC only altered ASIC currents and acid-induced increase in [Ca(2+)](i) in wild-type, but not in KO mice. In conclusion, our data provided the direct evidence from PICK1-KO mice that a novel target protein, PICK1, would regulate ASIC function and membrane expression in the brain. In addition, PICK1 played the bridge role between PKC and ASICs.

Tanshinone IIA attenuates neuronal damage and the impairment of long-term potentiation induced by hydrogen peroxide

AIM OF THE STUDY Tanshinone IIA (Tan IIA) is one of the key components of Salvia miltiorrhiza Bunge that has been widely used for various cardiovascular and cerebrovascular disorders in Asian countries. Many studies have reported that Tan IIA has antioxidative properties, but whether Tan IIA can rescue neurons from oxidative insult has never been reported. The present study was undertaken to evaluate the possible neuroprotective effects of Tan IIA on hydrogen peroxide (H(2)O(2))-induced oxidative stress in rats. MATERIALS AND METHODS H(2)O(2)-induced cytotoxicity was evaluated by the cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry with PI staining. Calcium imaging experiments were carried out to measure intracellular free calcium concentration. Western blotting was used to determine the expression of Bax and Bcl-2 protein. Electrophysiological studies in hippocampal slices were performed to investigate the effect of Tan IIA on synaptic function and cognitive impairment caused by H(2)O(2). RESULTS It was found that pretreatment with Tan IIA protected primary rat cortical neurons against H(2)O(2)-induced cytotoxicity. Furthermore, Tan IIA markedly reduced the elevation of [Ca(2+)](i) evoked by H(2)O(2). Western blot analysis indicated that pretreatment with Tan IIA prevented the increase in Bax/Bcl-2 ratio induced by H(2)O(2). In addition, preincubation of Tan IIA 20 min prior to H(2)O(2) exposure could reverse H(2)O(2)-induced hippocampal LTP impairment, but without significant alteration in basal synaptic transmission and LTP induction. CONCLUSIONS These findings demonstrate that Tan IIA might serve as a novel promising therapeutic agent for oxidative stress injury in neurodegenerative diseases.

The Stability of NR2B in the Nucleus Accumbens Controls Behavioral and Synaptic Adaptations to Chronic Stress

BACKGROUND The nucleus accumbens (NAc) is closely correlated with depression. It has been demonstrated that the glutamatergic system in NAc plays an important role in the reward pathway, dysfunction of which would cause anhedonia, a core symptom of depression. We therefore tested whether N-methyl-D-aspartate receptors and the synaptic plasticity in the NAc are regulated by chronic stress and the relevance to depression. METHODS We applied behavioral tests (n = 12, each group) of social interaction and sucrose preference tests to identify the susceptibility of mice to chronic social defeat stress. We then tested N-methyl-D-aspartate receptor-long-term depression at cortico-accumbal synapse to determine the relationship between the susceptibility and changes in synaptic plasticity (n = 8, each group). We further investigated whether restoration of these changes could produce antidepressant effects (n = 10). RESULTS We found that chronic stress induced selective downregulation of N-methyl-D-aspartate receptor NR2B subunits in the confined surface membrane pool of NAc neurons. Remarkably, the loss of synaptic NR2B was a long-lived event and further translated to the significant modulation of synaptic plasticity in the form of long-term depression. We further observed that the stress-induced changes were restored by fluoxetine and that resilient mice-those resistant to chronic stress-showed patterns of molecular regulation in the NAc that overlapped dramatically with those seen with fluoxetine treatment. Behaviorally, restoration of NR2B loss prevented the behavioral sensitization of mice to chronic stress. CONCLUSIONS Our results identify NR2B in the NAc as a key regulator in the modulation of persistent psychomotor plasticity in response to chronic stress.