Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling

Recent studies indicate that astrocytes play an integral role in neural and synaptic functioning. To examine the implications of these findings for neurobehavioral plasticity we investigated the involvement of astrocytes in memory and long-term potentiation (LTP), using a mouse model of impaired learning and synaptic plasticity caused by genetic deletion of the interleukin-1 receptor type I (IL-1RI). Neural precursor cells (NPCs), derived from either wild type (WT) or IL-1 receptor knockout (IL-1rKO) neonatal mice, were labeled with bromodeoxyuridine (BrdU) and transplanted into the hippocampus of either IL-1rKO or WT adult host mice. Transplanted NPCs survived and differentiated into astrocytes (expressing GFAP and S100β), but not to neurons or oligodendrocytes. The NPCs-derived astrocytes from WT but not IL-1rKO mice displayed co-localization of GFAP with the IL-1RI. Four to twelve weeks post-transplantation, memory functioning was examined in the fear-conditioning and the water maze paradigms and LTP of perforant path-dentate gyrus synapses was assessed in anesthetized mice. As expected, IL-1rKO mice transplanted with IL-1rKO cells or sham operated displayed severe memory disturbances in both paradigms as well as a marked impairment in LTP. In contrast, IL-1rKO mice transplanted with WT NPCs displayed a complete rescue of the impaired memory functioning as well as partial restoration of LTP. These findings indicate that astrocytes play a critical role in memory functioning and LTP, and specifically implicate astrocytic IL-1 signaling in these processes. The results suggest novel conceptualization and therapeutic targets for neuropsychiatric disorders characterized by impaired astrocytic functioning concomitantly with disturbed memory and synaptic plasticity.     

The role of interleukin-1 in seizures and epilepsy: A critical review

Interleukin-1 (IL-1) has a multitude of functions in the central nervous system. Some of them involve mechanisms that are related to epileptogenesis. The role of IL-1 in seizures and epilepsy has been investigated in both patients and animal models. This review aims to synthesize, based on the currently available literature, the consensus role of IL-1 in epilepsy.Three lines of evidence suggest a role for IL-1: brain tissue from epilepsy patients and brain tissue from animal models shows increased IL-1 expression after seizures, and IL-1 has proconvulsive properties when applied exogeneously. However, opposing results have been published as well. More research is needed to fully establish the role of IL-1 in seizure generation and epilepsy, and to explore possible new treatment strategies that are based on interference with intracellular signaling cascades that are initiated when IL-1 binds to its receptor.     

Testing the importance of the caudal retrosplenial cortex for spatial memory in rats

Although there is evidence to suggest that the retrosplenial cortex is involved in spatial learning and memory, many lesion studies have left the more caudal part of this region intact so leaving its role untested. In the first experiment, rats with neurotoxic lesions of the caudal half of the retrosplenial cortex (RspC1) were tested on a reference memory task in the water-maze. The RspC1 animals were impaired on initial acquisition although they performed normally on a subsequent probe test. The second experiment looked at working memory in the radial-arm maze and water-maze. Animals with caudal retrosplenial lesions (RspC2) were unimpaired on the acquisition stage of the radial-arm maze task but were impaired when the task involved maze rotation to control for the possible use of intramaze cues. The RspC2 animals also took longer to learn the platform position on a delayed matching-to-place task in the water-maze. These results show a subtle impairment in spatial memory performance that is not as severe as that seen when more complete lesions of the retrosplenial cortex are made.     

Immunoreactive interleukin-1β localization in the rat forebrain

To determine whether the cytokine, interleukin-1β, is present in the rat brain as has been reported in human brain, immunocytochemical studies were performed using an antiserum that recognizes recombinant, rat IL-1β. Immunoreaction product was present in the periventricular and medial hypothalamus, mossy fiber distribution in the hippocampus and olfactory tubercle. These studies demonstrate that IL-1β is part of a diffuse intrinsic neural system in the rat central nervous system, associated with regions involved with hypophysiotropic, autonomic, limbic and extrapyramidal functions.     

A dual role for interleukin-1 in LTP in mouse hippocampal slices

Interleukin-1 (IL-1) exerts numerous effects in the central nervous system and has been implicated in synaptic plasticity. The objective of this study was to investigate the role of endogenous as well as exogenous IL-1 on long-term potentiation (LTP). Hippocampal slices incubated at 34-36 degrees C show enhanced levels of IL-1alpha and IL-1beta compared to slices incubated at 21-24 degrees C. IL-1 inhibits LTP induced by theta-burst stimulation (TBS) at either temperature. IL-1 receptor antagonist (IL-1ra) had no effect on LTP at 21-24 degrees C, but displayed a concentration-dependent inhibition of LTP at 34-36 degrees C. Under control conditions, the magnitude of LTP was not temperature dependent. These data suggest that IL-1 is required for LTP under physiological conditions but at higher doses, as encountered in pathological conditions, IL-1 inhibits LTP.     

The role of cerebral noradrenergic systems in the Fos response to interleukin-1

Peripheral administration of interleukin-1 (IL-1) has been shown to activate induction of Fos in the brain, but the mechanism is not known. Because cerebral noradrenergic systems have been implicated in Fos induction, we studied the IL-1-induced appearance of Fos in mice pretreated with 6-hydroxydopamine (6-OHDA) which depleted cerebral norepinephrine (NE) by more than 90%, but did not significantly alter dopamine. Intraperitoneally injected IL-1β increased Fos in several brain regions, but most obviously in the hypothalamic paraventricular nucleus (PVN). Pretreatment with 6-OHDA substantially reduced the IL-1-induced Fos increase in the PVN which was no longer statistically significant. When the 6-OHDA treatment was preceded by administration of desmethylimipramine which prevents NE depletion, IL-1 treatment increased Fos in the PVN, suggesting that the effect of 6-OHDA was indeed related to the depletion of NE. These results suggest that the noradrenergic innervation of the PVN is involved in the IL-1-induced induction of Fos in the PVN. By contrast with previous experiments in rats, the IL-1-induced increase in plasma corticosterone was not significantly altered by the 6-OHDA pretreatment in mice.     

Formation of interleukin-6 in the brain of the febrile cat: relationship to interleukin-1

Previous investigations have shown that interleukin-6 (IL-6), unlike other cytokines, is produced in larger amounts in the brain of the febrile animal regardless of the route, peripheral vs. central, of pyrogen administration. In addition, depending on the experimental condition IL-6 production may or may not require the prior induction of interleukin-1 (IL-1). The present study was carried out in the conscious cat to assess the importance of brain-derived IL-6 in the pathogenesis of fever and the interaction at that site between this cytokine and IL-1. IL-6 was detected in cerebrospinal fluid (CSF) collected at rest and its levels increased during the fever to intravenous (i.v.) endotoxin. The IL-6 elevation, but not the fever, was reversed by pretreatment with intracerebroventricular (i.c.v.) IL-1 receptor antagonist (hIL-1ra). Conversely, when pyrogens (endotoxin, IL-1) were given i.c.v., i.c.v. hIL-1ra reduced the fever without altering significantly the associated rise in CSF IL-6. We conclude that IL-6 is formed in brain in response to both i.v. and i.c.v. pyrogens; however, its formation, whether requiring the prior induction of IL-1 or not, does not appear to be critical for the development of the fever. Blood-borne IL-6, unlike brain-derived IL-6, may still play a role in fever as a trigger of signal-transducing mechanisms operating across the blood–brain barrier.     

The role of interleukin-6 in the activation of the hypothalamo-pituitary-adrenocortical axis and brain indoleamines by endotoxin and interleukin-1β

Interleukin-6 (IL-6) is one of several cytokines that can stimulate the hypothalamo-pituitary-adrenocortical (HPA) axis. Because IL-6 is produced in response to the administration of endotoxin (LPS) and interleukin-1 (IL-1), it is possible that IL-6 contributes to the neuroendocrine and neurochemical changes induced by them. In this study, intraperitoneal (i.p.) injection of LPS elevated plasma concentrations of IL-6 while activating the HPA axis in a dose-dependent manner. Both responses reached a peak at around 2–3 h. Mouse IL-1β administration (100 ng, i.p.) induced large increases in plasma corticosterone and a substantial, but short-lived increase in plasma IL-6 with a peak at 2 h. Pretreatment of mice intraperitoneally with a monoclonal antibody to mouse IL-6 significantly attenuated the plasma ACTH and corticosterone responses to LPS at 3 h, but not at 1 h. Anti-IL-6 treatment also attenuated the LPS-induced increases of tryptophan and the serotonin catabolite, 5-hydroxyindoleacetic acid (5-HIAA), but not that of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG). Pretreatment of mice with anti-IL-6 significantly attenuated the IL-1-induced increases of plasma ACTH and corticosterone at 2 h, but not at 4 h. The IL-1-induced increases of MHPG, tryptophan and 5-HIAA in hypothalamus and brain stem were not significantly altered. These results suggest that IL-6 contributes to the later phases of the LPS- and IL-1-induced stimulations of the HPA axis and to the indoleaminergic responses to LPS, but not to IL-1.     

Possible role of the sympathetic nervous system in responses to interleukin-1

Interleukin-1 (IL-1) is a key mediator of changes in immune, endocrine and metabolic activities, collectively called the acute phase response, seen during infection and tissue injury. The purpose of the present study was to clarify a possible role of the sympathetic nervous system in the responses to IL-1 in rats. Intraperitoneal injection of IL-1 elicited an increase in rectal temperature and white blood cell count and a decrease in the plasma levels of glucose, iron and triglyceride. Pretreatment of rats with 6-hydroxydopamine or a ganglionic blocking agent abolished some of the responses, such as hypoglycemia and the increased white blood cell count. IL-1 injection also accelerated norepinephrine turnover, an index of sympathetic nerve activity, in the spleen and lung without appreciably affecting many other organs, such as the liver, heart, pancreas and brown adipose tissue. It was concluded that IL-1 activates the sympathetic nerves specifically in the spleen and lung, and can thereby influence the immune and metabolic functions of these organs.     

多发性硬化与白细胞介素-1关系初步研究

目的探讨白细胞介素-1(IL-1),尤其是白细胞介素-1β(IL-1β)和白细胞介素-1受体拮抗剂(IL-1RA)基因多态性及IL-1β血清含量与东北地区汉族多发性硬化(M S)的关系。方法多聚酶链反应(PCR)对54例M S患者的血清进行IL-1β和IL-1RA基因多态性检测;酶联免疫吸附实验检测血清中IL-1β含量。结果IL-1β和IL-1RA基因型分布及等位基因频率在M S和对照组间无显著性差异(P>0.05)。IL-1β血清含量M S组比对照组显著增高(P<0.05)。结论IL-1β和IL-1RA基因多态性与M S易感性可能无相关性。IL-1β可能在M S发病中起到促进作用,参与启动炎症过程和组织损伤。     

The role of hippocampus in memory: A hypothesis

The role of the hippocampus in memory storage in the mammalian brain is examined. The intrinsic anatomical organization of the hippocampus is such that a multidimensional mapping of other brain regions is represented. Emerging knowledge of the cortico-limbic-subcortical anatomy suggests that the hippocampal representations preserve the topological features of the targets and possess reciprocal connectivity. Long-Term Potentiation (LTP) is a prominent physiological characteristic of hippocampal synapses and is a promising candidate mnemonic device. The hypothesis is advanced that the pattern, or index, of specific neocortical (and other) areas activated by an experiential event is represented, or indexed, in the hippocampus by means of LTP. This hypothesis, termed the Memory Indexing Theory, suggests that experiential events are initially stored in an index of neocortical locations maintained in hippocampus. Subsequently, other regions, notably neocortex itself, permanently encode these experiential events and the interrelationships between them.     

Permissive role of glucocorticoids on interleukin-1 activation of the hypothalamic serotonergic system

The present study analyses the effect of IL-1β (10 ng i.c.v.) on the hypothalamic serotonergic system and the modulatory role of glucocorticoids. Changes in the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) were recorded in freely moving rats by in vivo voltammetry using chronically implanted carbon fiber electrodes (8 μm) in the medial preoptic area. IL-1β induced a dual increase in 5HIAA levels: a rapid, short-term rise was followed by a lasting increase possibly due to newly synthesized IL-1. The synthetic glucocorticoid dexamethasone (DEX, 3 mg/kg i.p., 30 min before IL-1β), prevented the effect of IL-1β starting from 150 min, suggesting that it only inhibited the second increase. In adrenalectomized rats IL-1β had no effect but when these rats were given DEX (40 μg/kg a day for 3 days) the short-term increase was restored. The glucocorticoid receptor antagonist RU38486 (25 mg/kg s.c., 60 min before IL-1β) completely prevented IL-1β activation of the serotonergic system. The results indicate that the glucocorticoids are effective inhibitors of IL-1 synthesis but that they play a permissive role on IL-1β induced activation of the serotonergic system.     

Contribution of interleukin-1beta in neuropathic pain

炎性因子白细胞介素-1β(IL-1β)参与神经病理性疼痛的中枢和周围敏化过程,此为其特征性病理变化.IL-1β是介导中枢神经系统胶质细胞与神经元相互作用的重要炎性因子,其活化受到其他炎性因子的调控,如趋化细胞因子配体2(CCL2)和基质金属蛋白酶2、9(MMP-2、9)等.本文简要概述IL-1β在中枢性和周围性神经病理性疼痛中的主要作用机制.     

抑郁症患者血清白细胞介素-1β,6的水平及其发病机制的对照研究

目的　探讨抑郁症的细胞免疫改变及其可能的发病机制。方法　采用酶联免疫吸附法 ,对 31例抑郁症患者在抗抑郁治疗前后分别进行HAMD评定及IL - 1β ,IL - 6的检测 ,并以 2 1例健康者作对照。 结果　抑郁症治疗前IL - 1β及IL - 6水平显著高于正常对照组 (P <0 0 5 ) ,且经 4～ 10周左右治疗后 ,二者明显下降。但疗前HAMD评分高低与疗前IL - 1β及IL - 6水平并无相关性 (P >0 0 5 )。 结论　免疫系统激活及炎症反应确实参与抑郁症的发病过程 ,但本研究尚不能确定抑郁症严重度 (HAMD评分 )与血清IL - 1β及IL - 6水平存在相关性。     

Production of interleukin-1 by microglia in response to substance P: role for a non-classical NK-1 receptor

Substance P (SP) is a central and peripheral neurotransmitter which has been found in multiple sclerosis plaques. SP stimulates peripheral immune cells and may play a role in some chronic inflammatory diseases. Human peripheral monocyte/macrophages have been shown to produce the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) in response to SP. Therefore, in this study we examined rat brain microglia for the presence of SP receptors and production of IL-1 and TNFα in response to SP. Microglia had 4900±950(mean ± SE) receptors per cell fitting a two-site model. Four percent of these were high-affinity receptors with a K_d of 8.2 × 10⁻⁸ M ± 3.6 × 10⁻⁸ M (mean ± SE), and 96% of them were low-affinity receptors with a K_d of 2.1 × 10⁻⁶ M ± 5.2 × 10⁻⁷ M (mean ± SE). Competitive studies with CP 96,345 and other SP analogs demonstrate these to be non-classical NK-1 receptors. SP alone did not stimulate IL-1 or TNFα production. However, SP in synergy with lipopolysaccharide (LPS) quadrupled IL-1 production compared to LPS alone, but did not affect TNFα production. These results have implications for certain inflammatory conditions in the central nervous system.     

Human immunodeficiency virus-1 coat protein gp120 impairs contextual fear conditioning: a potential role in AIDS related learning and memory impairments

Many AIDS patients suffer from cognitive impairments including deficits in learning and memory. The Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein gp120 is one possible mediator of these impairments. This is because gp120 activates brain microglial cells and astrocytes, and in vivo activation of glia leads to the release of the proinflammatory cytokine interleukin-1 beta (IL-1β). gp120 induced IL-1β release could be involved in producing memory impairments associated with AIDS because central IL-1β activity adversely affects cognitive function. The reported experiments evaluated the effects of i.c.v. gp120 administration and subsequent IL-1β activity on learning and memory processes in the rat. Intracerebroventricular gp120 produced memory impairments on hippocampally dependent contextual fear conditioning, but not hippocampally independent auditory-cue fear conditioning following post-conditioning gp120 administration. Central gp120 administration also caused increases in IL-1β protein levels in the hippocampus and frontal cortex but not in the hypothalamus. gp120 induced memory impairments were blocked by 2 different IL-1 antagonists, alpha melanocyte stimulating hormone (αMSH) and interleukin-1 receptor antagonist (IL-1ra). Finally, heat denaturation of the tertiary structure of gp120 abolished its effects on fear conditioning, suggesting that gp120 impairs contextual fear conditioning by binding to its receptors on glia.     

Antibodies to interleukin-1 inhibit cytokine-induced proliferation of neonatal rat Schwann cells in vitro

Unfractionated cytokines have been shown to induce in vitro proliferation of neonatal rat Schwann cells but the nature of the mitogen(s) is not known. A mixture of rabbit antibodies specific for recombinant interleukin-1α (IL-1α) and interleukin-1β (IL-1β) inhibited Schwann cell proliferation induced by unfractionated human cytokines whereas antibodies to interleukin-2 (IL-2) and control IgG did not. However, purified human IL-1 and recombinant human IL-1α or β did not induce Schwann cell proliferation on their own.     

The role of interleukin-1 and tumor necrosis factor α in the neurochemical and neuroendocrine responses to endotoxin

Both interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) are potent activators of the hypothalamo-pituitary-adrenal (HPA) axis, and they also increase cerebral norepinephrine metabolism and tryptophan. Injections of cause macrophages to synthesize and release various cytokines, including IL-1 and tumor necrosis factor α (TNFα). The hypothesis that macrophage production of IL-1 mediates the HPA-activating effect of LPS was tested in mice using the IL-1-receptor antagonist protein (IRAP). Administration of IRAP largely prevented the effects of IL-1α or IL- 1β on the elevation of plasma corticosterone and the concomitant increase in hypothalamic norepinephrine metabolism, but failed to alter the responses to LPS. IRAP did not prevent the increases in brain tryptophan that occurred after treatment with IL-1 or LPS. Recombinant human TNFa, TNFβ, IL-6, and interferon-a injected intraperitoneally failed to activate the HPA axis, but mouse TNFa was effective by this route, and human TNFα, TNFβ, and IL-6 were effective intravenously. None of these cytokines was as potent as IL-1. Pretreatment with an antibody specific for mouse TNFα, either alone or in combination with IRAP, also failed to prevent the elevation of plasma corticosterone by LPS. Thus, either IL-1 and TNFα are not involved in the HPA and noradrenergic responses to LPS, or there are alternative (redundant) pathways by which LPS can activate the HPA axis.     

Potential mechanisms of interleukin-1 involvement in cerebral ischaemia

Interleukin-1 (IL-1) has pleiotropic actions in the central nervous system. During the last decade, a growing corpus of evidence has indicated an important role of this cytokine in the development of brain damage following cerebral ischaemia. The expression of IL-1 in the brain is dramatically increased during the early and chronic stage of infarction. The most direct evidence that IL-1 contributes significantly to ischaemic injury is that (1) central administration of IL-1β exacerbates brain damage, and (2) injection or over-expression of interleukin-1 receptor antagonist, and blockade of interleukin-1β converting enzyme activity reduce, dramatically, infarction and improve behavioural deficit. The mechanisms underlying IL-1 actions in stroke are not definitively elucidated, and it seems likely that its effects are mediated through stimulation and inhibition of wide range of pathophysiological processes.