Flip side of synaptic plasticity: Long-term depression mechanisms in the hippocampus

There is growing interest in the phenomenon of long-term depression (LTD) of synaptic efficacy that, together with long-term potentiation (LTP), is a putative information storage mechanism in mammalian brain. In neural network models, multiple learning rules have been used for LTD induction. Similarly, in neurophysiological studies of hippocampal synaptic plasticity, a variety of activity patterns have been effective at inducing LTD, although experimental paradigms are still being optimized. In this review the authors summarize the major experimental paradigms and compare what is known about the mechanisms of LTD induction. Although all paradigms appear to initiate a cascade of events leading to an elevated level of Ca²⁺ postsynaptically, the extent to which these paradigms involve common expression mechanisms has not yet been tested. The authors discuss several critical experiments that would address this latter issue. Numerous questions about the properties and mechanisms of LTD(s) in the hippocampus remain to be answered, but it is clear that LTD has finally arrived, and will soon be attracting attention equal to its flip side, LTP. © 1994 Wiley-Liss, Inc.     

Glutamergic Action on Alpha-Melanocyte-Stimulating Hormone Release from the Rat Hypothalamus

Release of α-melanocyte-stimulating hormone (α-MSH) synthesized in the hypothalamus is regulated by monoaminergic neuronal systems. An endogenous dopaminergic system inhibits α-MSH release (1, 2) whilst serotoninergic systems exert a biphasic effect on peptide release (3). The toxic effects of neonatal peripheral administration of monosodium glutamate on hypothalamic neurons containing proopiomelanocortin- (POMC-) derived peptides (4, 5) suggest additionally the presence of glutamate receptors on or indirectly influencing the POMC neuron. By comparison of the effect of the excitatory amino-acid agonists N-methyl-D-aspartate (NMDA), quisqualate and kainate on the release of α-MSH from superfused slices of rat hypothalamus, we have demonstrated a stimulatory glutamergic action on α-MSH release mediated through NMDA-type receptors.     

Microarray analysis of healing rat Achilles tendon: evidence for glutamate signaling mechanisms and embryonic gene expression in healing tendon tissue.

Tendon healing is a complex process consisting of a large number of intricate pathways roughly divided into the phases of inflammation, proliferation, and remodeling. Although these processes have been extensively studied at a variety of levels in recent years, there is still much that remains unknown. This study used microarray analyses to investigate the process at a genetic level in healing rat Achilles tendon at 1, 7, and 21 days postinjury, roughly representing the inflammation, proliferation, and remodeling phases. An interesting temporal expression profile was demonstrated, identifying both known and novel genes and pathways involved in the progression of tendon healing. Both inflammatory response and pro-proliferative genes were shown to be significantly upregulated from 24 h postinjury through to 21 days. Day 7 showed the largest increase in genetic activity, particularly with the expression of collagens and other extracellular matrix genes. Interestingly, there was also evidence of central nervous system-like glutamate-based signaling machinery present in tendon cells, as has recently been shown in bone. This type of signaling mechanism has not previously been shown to exist in tendon. Another novel finding from these analyses is that there appears to be several genes upregulated during healing which have exclusively or primarily been characterized as key modulators of proliferation and patterning during embryonic development. This may suggest that similar pathways are employed in wound healing as in the tightly regulated progression of growth and development in the embryo. These results could be of use in designing novel gene-based therapies to increase the efficacy and efficiency of tendon healing.     

The Glutamatergic Innervation of Oxytocin- and Vasopressin-secreting Neurons in the Rat Supraoptic Nucleus and its Contribution to Lactation-induced Synaptic Plasticity

The present ultrastructural study analysed the distribution of glutamatergic synapses on oxytocin- and vasopressin-secreting neurons in the rat supraoptic nucleus (SON) after post-embedding immunogold labelling for glutamate and GABA, oxytocin or vasopressin. About 20% of SON axo—somatic synapses were enriched in glutamate immunoreactivity, visible over synaptic-like vesicles, mitochondria and synaptic densities. Double labelling for glutamate and GABA showed that putative glutamatergic terminals were distinct from GABAergic terminals. In ultrathin sections stained for glutamate and either oxytocin or vasopressin, the proportion of glutamatergic synapses was similar on oxytocinergic and vasopressinergic somata in virgin rats under basal conditions of peptide release as well as in lactating rats, in which oxytocin secretion is enhanced. Cross-sectional soma areas were significantly increased in lactating rats: oxytocinergic profiles were, on average, ˜40% larger than in virgin rats. However, the incidence of axo—somatic glutamatergic synapses (assessed as mean number of synapses per 100 μm of plasmalemma or proportion of somatic surface apposed to synaptic active zones) did not diminish, indicating that there was a compensatory increase of synapses during lactation. Also, we found an increase in the number of glutamatergic terminals making synaptic contact simultaneously onto two or more oxytocinergic elements in the same plane of section. Our observations therefore indicate that SON oxytocinergic and vasopressinergic neurons are innervated to a similar extent by a relatively large proportion of glutamatergic synapses. They reveal, moreover, that glutamatergic afferents participate in the lactation-induced synaptic plasticity of the oxytocinergic system.     

谷氨酸脱氢酶,胆碱氧化酶和葡萄糖-6-磷酸酶对溶酶体中~(67)Ga积累的影响(英文)

目的:比较正常肝组织与肝癌AH 109A,吉田肉瘤中谷氨酸脱氢酶,胆碱氧化酶和葡萄糖-6-磷酸酶的活力对~(67)Ga摄取与积累的影响;方法:制备~(67)Ga枸橼酸溶液给大鼠静注后处死大鼠,制备亚细胞悬液,液闪计数器测定放射活度.结果:~(67)Ga的放射活性在正常肝组织溶酶体中(55％积聚)显著高于肝癌AH109A(32％积聚)和吉田肉瘤(18％)积聚.谷氨酸脱氢酶的活力在正常肝组织,肝癌和吉田肉瘤分别是1830±s 320 U·L~(-1),23±s 6 U·L~(-1)和7±s 2 U·L~(-1);胆碱氧化酶的活力分别是46±s 10 U·L~(-1),25.0±s 0.4 U·L~(-1),2.0±0.4 U·L~(-1);葡萄糖-6-磷酸酶活力分别是2550±s 180 U·L~(-1),84±s 14 U·L~(-1),78±s13 U·L~(-1).结论:正常肝组织中溶酶体酶活力很强,对~(67)Ga的积累起较大作用.癌变组织酶活力降低而作用减弱.吉田肉瘤细胞无肝细胞特点,其溶酶体对~(67)Ga积累作用不大.     

Alterations of G-protein Coupling Function in Phosphoinositide Signalling Pathways of Rat Hippocampus by Ischaemic Brain Injury

The activation of membrane-associated phospholipase C is rapidly and transiently induced in the central nervous system by a variety of stimuli. Ischaemic brain injury is one of the situations that leads to a dramatic increase in polyphosphoinositide (PPI) turnover. In this study, stimulation of PPI hydrolysis by glutamate (500 μM) was measured in hippocampal slices from rats up to 21 days after an ischaemic insult of 30 min. Ischaemia was induced using the four-vessel occlusion method. PPI hydrolysis elicited by glutamate was significantly increased in the slices prepared from ischaemic rats 24 h after reperfusion, the accumulation of inositol phosphates (InsP_s) and inositol 1,4,5-trisphosphate (InsP₃) was 614±74% ( n = 8) and 182±11% ( n = 9) of the basal level respectively. This potentiation was also observed 21 days after ischaemia. Hyper-responsiveness to glutamate was also accompanied by an increase in AIF⁻₄-stimulated formation of [³H]inositol phosphates. In addition, global ischaemia did not change either high-affinity [³H]glutamate binding in hippocampal membranes or the stimulation of PPI hydrolysis by carbachol or noradrenaline in hippocampal slices. The present results suggest that the increased responsiveness to glutamate is the result, at least in part, of functional changes at the G-protein level, and may contribute to the pathophysiology of ischaemic brain injury or to the regenerative phenomena that accompany ischaemic damage.     

INVOLVEMENT OF NON-NMDA AND NMDA RECEPTORS IN GLUTAMATE-INDUCED PRESSOR OR DEPRESSOR RESPONSES OF THE PONS AND MEDULLA

1. Fifty-five intact and six baroreceptor denervated and vagotomized cats of either sex were anaesthetized intraperito-neally with urethane (400 mg/kg) and a-chloralose (40 mg/kg). Responses of the systemic arterial pressure (SAP), mean SAP (MSAP) and sympathetic vertebral nerve (VNA) and renal nerve activities (RNA) were recorded. 2. In intact animals, monosodium L-glutamate (Glu, 0.1 mol/L, 50 nL) was microinjected into pressor areas of the locus coeruleus (LC), gigantocellular tegmental field (GTF), rostral ventrolateral medulla (RVLM) and dorsomedial medulla (DM), and the depressor areas of caudal ventrolateral medulla (CVLM). The induced actions were compared before and after microinjection of either glutamate antagonists, glutamate diethylester (GDEE, 0.5 mol/L, 50–100nL), a competitive AMPA receptor blocker, or 2-amino-5-phosphonovaleric acid (D-AP5, 0.025 mol/L, 50–100 nL), a competitive N-methyl-D-aspartate (NMDA) receptor blocker. GDEE completely blocked the increases of SAP and VNA elicited from all pressor areas. D-AP5 only partially blocked the pressor but slightly blocked VNA and RNA responses from LC, GTF and DM, particularly those from RVLM. Neither GDEE nor D-AP5 blocked the depressor responses of SAP and two nerve activities elicited from CVLM. 3. In baroreceptor denervated animals, NMDA (2 mmol/L, 50–100 nL) and AMPA (0.2 mmol/L, 50–100 nL) were micro-injected into the same pressor areas of GTF, RVLM and DM and the depressor area of CVLM responsive to Glu activation (0.1 mol/L, 30 nL). In RVLM, DM and CVLM, the results of either NMDA or AMPA were similar to those induced by Glu. However, in GTF, microinjection of either NMDA or AMPA did not induce similar responses to Glu. This suggests that the nature of GTF may differ from RVLM and DM. 4. The above results suggest that the Glu-induced pressor responses from LC, GTF, DM and especially RVLM, are primarily mediated through AMPA receptors. The Glu-induced depressor responses from CVLM may not be predominantly mediated by either AMPA or NMDA receptors. 5. In both baroreceptor-intact and -denervated cats stimulation of the pressor areas often produced an increase of VNA and a decrease of RNA, while in the depressor CVLM decreased both VNA and RNA. The VNA, but not RNA were positively correlated with the pressor responses, while both VNA and RNA were positively correlated with the depressor responses. This may suggest that neurons of the sympathetic vertebral and renal nerves are topographically organized in the brain.     

The effect of the synthetic neuroprotective dipeptide noopept on glutamate release from rat brain cortex slices

The level of spontaneous and K⁺-stimulated release of endogenous glutamate was studied in experiments on slices of brain cortex of Wistar rats. Pronounced spontaneous release of the neuromediator and its increase under conditions of stimulation were registered by high-performance liquid chromatography with electrochemical detection. The effect of the nootropic and neuroprotective dipeptide Noopept (GVS-111) on release of glutamate was investigated. The peptide in concentrations of 10^?5 and 10^?6 M caused a statistically significant decrease in spontaneous and K⁺-stimulated glutamate release. This effect could be the basis of the neuroprotective action of the peptide, suggesting that further studies of Noopept as neuroprotector are very promising.     

Role of group II and group III metabotropic glutamate receptors in spinal cord injury.

Spinal cord injury (SCI) produces an increase in extracellular excitatory amino acid (EAA) concentrations that results in glutamate receptor-mediated excitotoxic events. An important class of these receptors is the metabotropic glutamate receptors (mGluRs). mGluRs can activate a number of intracellular pathways that increase neuronal excitability and modulate neurotransmission. Group I mGluRs are known to modulate EAA release and the development of chronic central pain (CCP) following SCI; however, the role of group II and III mGluRs remains unclear. To begin evaluating group II and III mGluRs in SCI, we administered the specific agonists for group II, APDC, or group III, L-AP4, by interspinal injection immediately following SCI. Contusion injury was produced at spinal segment T10 with a New York University impactor (12.5-mm drop, 10-g rod 2 mm in diameter) in 30 adult male Sprague-Dawley rats (175-200 g). Evoked and spontaneous behavioral measures of CCP, locomotor recovery, changes in mGluR expression, and amount of spared tissue were examined. Neither APDC nor L-AP4 affected locomotor recovery or the development of thermal hyperalgesia; however, L-AP4 and APDC attenuated changes in mechanical thresholds and changes in exploratory behavior indicative of CCP. APDC- and L-AP4-treated groups had higher expression levels of mGluR2/3 at the epicenter of injury on post contusion day 28; however, there was no difference in the amount of spared tissue between treatment groups. These results demonstrate that treatment with agonists to group II and III mGluRs following SCI affects mechanical responses, exploratory behavior, and mGluR2/3 expression without affecting the amount of tissue spared, suggesting that the level of mGluR expression after SCI may modulate nociceptive responses.     

力竭运动后大鼠海马脑区谷氨酸受体NR2A蛋白含量和基因表达的变化

目的:观察力竭运动前后大鼠脑中海马谷氨酸受体NR2A蛋白含量和基因表达的变化,探讨其与运动性疲劳的可能联系。方法:50只SD雄性大鼠,随机分为安静对照组(S,n=10),力竭运动后即刻组(AE1,n=10),力竭运动后恢复0.5小时组(AE2,n=10),力竭运动后恢复3小时组(AE3,n=10)和力竭运动后恢复24小时组(AE4,n=10)。分别采用免疫印迹法和RT-PCR法测定一次性力竭运动后大鼠脑中海马谷氨酸受体NR2A蛋白含量和基因表达。结果:与安静对照组相比,力竭运动后即刻,大鼠NR2A蛋白含量明显升高,而mRNA表达显著减少;恢复0.5小时后,蛋白含量略有下降,mRNA表达显著增加;恢复3小时后蛋白含量显著下降,mRNA表达继续增加;恢复24小时后蛋白含量恢复到安静时水平,mRNA表达则减少至恢复0.5小时后水平。结论:力竭运动后即刻及恢复过程中,大鼠脑中海马谷氨酸受体NR2A蛋白含量及mRNA表达变化趋势不同,提示基因表达对蛋白含量的调控可能具有延迟性。