代谢型谷氨酸受体在突触可塑性中的作用

突触可塑性是近几年神经科学研究的热点之一,因为它对于理解神经系统的学习、学习和记忆、多咱神经疾病等许多过程有着重要的意义。除了离子型谷氨酸受体外,代谢型谷氨酸受体也参与了一些脑区中不同形式的突触可塑性变化。本文就代谢型谷氨酸受体选择性激动剂和拮抗剂对长时程增强和长时程抑制的作用进行了综述,以助于人们进一步理解突触可塑性的细胞和分子机制。     

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.

     

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.     

Cell‐specific changes in expression of mRNAs encoding splice variants of Aplysia cell adhesion molecule accompany long‐term synaptic plasticity

Aplysia neurons express several splice variants of apCAM, a member of the Ig superfamily of cell adhesion molecules. The major transmembrane isoform is endocytosed in sensory neurons (SNs) during the early phases of long‐term facilitation (LTF) of SN synapses evoked by serotonin (5‐HT) or in the motor neuron L7 during the early phases of long‐term depression (LTD) of SN synapses evoked by Phe‐Met‐Arg‐Phe‐amide (FMRFa). We used single cell RT‐PCR to evaluate whether expression of mRNAs encoding for different apCAM isoforms in SNs and L7 is regulated during LTF produced by 5‐HT, and LTD produced by FMRFa. Single SNs and L7s express mRNAs encoding for all major isoforms, but the proportion of each isoform expressed differs for the two cells. SN expresses more mRNA encoding for GPI‐linked isoforms, while L7 expresses more mRNA encoding for the major transmembrane isoform. The neuromodulators produced significant changes in the proportional levels of mRNAs encoding for specific apCAM isoforms during the first 4 h after treatments without affecting overall levels of apCAM mRNA. 5‐HT evoked changes that exaggerated cell‐specific differences in isoform expression. FMRFa evoked changes that reduced cell‐specific differences in isoform expression. The effects of the neuromodulators on apCAM mRNA expression were not detected when cells were cultured alone or when SNs were cocultured with another motor cell that failed to induce synapse formation (L11). The results suggest that rapid cell‐specific regulation of splice variant expression may contribute to different forms of long‐term synaptic plasticity. © 2000 John Wiley & Sons, Inc. J Neurobiol 45: 152–161, 2000     

Reduced SNAP‐25 alters short‐term plasticity at developing glutamatergic synapses

SNAP‐25 is a key component of the synaptic‐vesicle fusion machinery, involved in several psychiatric diseases including schizophrenia and ADHD. SNAP‐25 protein expression is lower in different brain areas of schizophrenic patients and in ADHD mouse models. How the reduced expression of SNAP‐25 alters the properties of synaptic transmission, leading to a pathological phenotype, is unknown. We show that, unexpectedly, halved SNAP‐25 levels at 13–14 DIV not only fail to impair synaptic transmission but instead enhance evoked glutamatergic neurotransmission. This effect is possibly dependent on presynaptic voltage‐gated calcium channel activity and is not accompanied by changes in spontaneous quantal events or in the pool of readily releasable synaptic vesicles. Notably, synapses of 13–14 DIV neurons with reduced SNAP‐25 expression show paired‐pulse depression as opposed to paired‐pulse facilitation occurring in their wild‐type counterparts. This phenotype disappears with synapse maturation. As alterations in short‐term plasticity represent a new mechanism contributing to cognitive impairments in intellectual disabilities, our data provide mechanistic clues for neuronal circuit alterations in psychiatric diseases characterized by reduced expression of SNAP‐25.     

Rapid bidirectional modulation of mRNA expression and export accompany long‐term facilitation and depression of Aplysia synapses

Serotonin (5‐HT) and the neuropeptide Phe‐Met‐Arg‐Phe‐amide (FMRFa) modulate synaptic efficacy of sensory neurons (SNs) of Aplysia in opposite directions and for long duration. Both long‐term responses require changes in mRNA and protein synthesis. The SN‐specific neuropeptide, sensorin A, is a gene product that appears to be increased by 5‐HT and decreased by FMRFa. We examined whether changes in sensorin A mRNA levels in the cell body and neurites of SNs accompany long‐term facilitation and depression. Both 5‐HT and FMRFa evoked rapid changes in sensorin A mRNA levels in the SN cell bodies: an increase with 5‐HT and a decrease with FMRFa. Parallel changes in sensorin A mRNA levels in SN neurites were detected 2 h and 4 h later. These rapid changes in mRNA expression and net export required the presence of the appropriate target motor cell L7. The neuromodulators failed to produce changes in mRNA expression or export when SNs were cultured alone or with the inappropriate target cell L11. The changes in mRNA expression were transient because mRNA levels returned to control values 24 h after treatment, while synaptic efficacy remained altered by the respective treatments. These results indicate that two neuromodulators produce distinct, but transient, target‐dependent effects on expression and export of a cell‐specific mRNA that correlate with changes in synaptic plasticity. © 2000 John Wiley & Sons, Inc. J Neurobiol 46: 41–47, 2001     

Experience‐related reorganization of giant synapses in the lateral complex: Potential role in plasticity of the sky‐compass pathway in the desert ant Cataglyphis fortis

Cataglyphis desert ants undergo an age‐related polyethism from interior workers to relatively short‐lived foragers with remarkable visual navigation capabilities, predominantly achieved by path integration using a polarized skylight‐based sun compass and a stride‐integrating odometer. Behavioral and physiological experiments revealed that the polarization (POL) pattern is processed via specialized UV‐photoreceptors in the dorsal rim area of the compound eye and POL sensitive optic lobe neurons. Further information about the neuronal substrate for processing of POL information in the ant brain has remained elusive. This work focuses on the lateral complex (LX), known as an important relay station in the insect sky‐compass pathway. Neuroanatomical results in Cataglyphis fortis show that LX giant synapses (GS) connect large presynaptic terminals from anterior optic tubercle neurons with postsynaptic GABAergic profiles of tangential neurons innervating the ellipsoid body of the central complex. At the ultrastructural level, the cup‐shaped presynaptic structures comprise many active zones contacting numerous small postsynaptic profiles. Three‐dimensional quantification demonstrated a significantly higher number of GS (～13%) in foragers compared with interior workers. Light exposure, as opposed to age, was necessary and sufficient to trigger a similar increase in GS numbers. Furthermore, the increase in GS numbers was sensitive to the exclusion of UV light. As previous experiments have demonstrated the importance of the UV spectrum for sky‐compass navigation in Cataglyphis, we conclude that plasticity in LX GS may reflect processes involved in the initial calibration of sky‐compass neuronal circuits during orientation walks preceding active foraging. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 390–404, 2016     

Activation of receptors negatively coupled to adenylate cyclase is required for induction of long‐term synaptic depression at Schaffer collateral‐CA1 synapses

Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral‐CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2′R,3′R)‐2‐(2′,3′‐dicarboxy‐cyclopropyl) glycine (DCGIV; 5 μM), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 μM), resulted in a long‐lasting depression of synaptic strength. When zaprinast (20 μM) was combined with a cell‐permeant PKA inhibitor H‐89 (10 μM), the need for mGluR IIs was bypassed. DCGIV, when combined with a “submaximal” low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)‐alpha‐ethylglutamic acid (EGLU; 5 μM), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)‐a‐Cyclopropyl‐[3‐³H]‐4‐phosphonophenylglycine (CPPG; 10 μM), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N⁶‐cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 μM), was sufficient to elicit CLTD. Inhibition of PKA with H‐89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2006     

Stimulation of GluN receptors decreases the surface density of GluN1/GluN2B subunits in cultured neocortical interneurons

Changes in the density of NMDA (GluN) receptors in the neuronal membrane are critical for plasticity, whereas malfunction of precisely regulated GluN receptor activity may be involved in neurotoxicity. In cultured rat neocortical interneurons, we have studied the regulation of the surface density of GluN1, GluN2A and GluN2B subunits. Application of 5 μMol NMDA for 24 h followed by a washout period of 24 h decreased the response of GluN receptors for at least 2?days. The reduction was caused by a decrease in the surface density of GluN1/GluN2B subunits, whereas GluN2A subunits remained unaffected. Our data indicate that long but reversible low level activation of GluN receptors can cause long-term changes in their subunit composition in cultured interneurons.     

EGb761对血管性痴呆大鼠海马突触可塑性的影响

目的：探讨银杏叶提取物（EGb761）对血管性痴呆（VD）模型大鼠海马突触可塑性的影响。方法：Morris水迷宫检测大鼠空间学习记忆能力;电生理学方法在体记录大鼠海马长时程增强。结果：各时间点模型组大鼠的逃逸潜伏期（EL）均较假手术组明显延长（P〈0.01）,药物组各亚组大鼠的EL均显著短于模型组（P〈0.01）,但仍长于假手术组（P〈0.01,P〈0.05）。模型组各亚组大鼠长时程增强（LTP）诱导率显著低于假手术组和药物组（P〈0.01）。模型组大鼠各时间点群发峰电位（PS）的相对幅值明显低于假手术组和药物组（P〈0.01,P〈0.05）。假手术组、模型组和药物组各时间点的PS潜伏期无显著差别。结论：VD模型大鼠长时间存在空间学习记忆障碍,EGb761能促进VD模型大鼠海马病理性突触可塑性的恢复,这可能是其促智作用的重要机制。     

Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice

Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35(-/-) mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35(-/-) mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35(-/-) mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which co-localized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39.     

Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation

Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous D-serine. Chronic treatment with L-NAC, but not acute application of the reducing agent, restored potent D-serine-dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in D-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the D-serine-dependent pathway.     

Protease‐activated receptor‐1 modulates hippocampal memory formation and synaptic plasticity

Protease‐activated receptor‐1 (PAR1) is an unusual G‐protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1?/? mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1?/? mice have deficits in hippocampus‐dependent memory. We also show that while PAR1?/? mice have normal baseline synaptic transmission at Schaffer collateral‐CA1 synapses, they exhibit severe deficits in N‐methyl‐d ‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR‐mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR‐dependent processes subserving memory formation and synaptic plasticity.     

Zinc-triggered induction of tissue plasminogen activator by brain-derived neurotrophic factor and metalloproteinases

Tissue plasminogen activator (tPA) is necessary for hippocampal long-term potentiation. Synaptically released zinc also contributes to long-term potentiation, especially in the hippocampal CA3 region. Using cortical cultures, we examined whether zinc increased the concentration and/or activity of tPA. Two hours after a 10-min exposure to 300 μM zinc, expression of tPA and its substrate, plasminogen, were significantly increased, as was the proteolytic activity of tPA. In contrast, increasing extracellular or intracellular calcium levels did not affect the expression or secretion of tPA. Changing zinc influx or chelating intracellular zinc also failed to alter tPA/plasminogen induction by zinc, indicating that zinc acts extracellularly. Zinc-mediated extracellular activation of matrix metalloproteinase (MMP) underlies the up-regulation of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (Trk) signaling. Consistent with these findings, co-treatment with a neutralizing antibody against BDNF or specific inhibitors of MMPs or Trk largely reversed tPA/plasminogen induction by zinc. Treatment of cortical cultures with p-aminophenylmercuric acetate, an MMP activator, MMP-2, or BDNF alone induced tPA/plasminogen expression. BDNF mRNA and protein expression was also increased by zinc and mediated by MMPs. Thus, an extracellular zinc-dependent, MMP- and BDNF-mediated synaptic mechanism may regulate the levels and activity of tPA.