Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oestrogens have numerous effects on the brain, beginning during gestation and continuing on into adulthood. Many of these actions involve areas of the brain that are not primarily involved in reproduction, such as the basal forebrain, hippocampus, caudate putamen, midbrain raphe and brainstem locus coeruleus. This paper describes three actions of oestrogens that are especially relevant to brain mechanisms involved in memory processes and their alterations during ageing and neurodegenerative diseases: (1) the regulation of cholinergic neurons by oestradiol in the rat basal forebrain, involving induction of choline acetyltransferase and acetylcholinesterase according to a sexually dimorphic pattern; (2) the regulation of synaptogenesis in the CA1 region of the hippocampus by oestrogens and progestins during the four- to five-day oestrus cycle of the female rat. Formation of new excitatory synapses is induced by oestradiol and involves N-methyl-D-aspartate receptors; removal of these synapses involves intracellular progestin receptors; (3) sex differences in hippocampal structure, which may help to explain differences in the strategies that male and female rats use to solve spatial navigation problems. During the period of development when testosterone is elevated in the male, aromatase and oestrogen receptors are also elevated, making it likely that this pathway is involved in the masculinization of hippocampal structure.
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PMID:Oestrogens and the structural and functional plasticity of neurons: implications for memory, ageing and neurodegenerative processes. 858 5

In the present study, variations of cholinergic and GABAergic markers in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) and the hippocampus of eight different inbred mouse strains were investigated. By means of immunocytochemistry against the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT), the cholinergic neurons were visualized and the number of ChAT-positive neuronal profiles in the MS/vDB was counted. Cholinergic and GABAergic septo-hippocampal projection neurons were detected with a combined retrograde tracing and immunocytochemical approach. In order to quantify the cholinergic innervation of various hippocampal sub-regions, we estimated the density of acetylcholinesterase (AChE)-containing fibers as visualized by AChE histochemistry. Additionally, the densities of muscarinic receptors (mainly the subtypes M1 and M2) in different hippocampal areas of seven inbred strains were measured by means of quantitative receptor autoradiography. We found significant strain differences for the number of ChAT-positive neurons in the MS/vDB; in the numbers of cholinergic septo-hippocampal projection neurons; in the density of cholinergic fibers in hippocampal subfields CA3c, CA1, and in the dentate gyrus; and in the density of muscarinic receptors in the hippocampus. In contrast the GABAergic component of the septo-hippocampal projection did not differ between the strains investigated. The number of ChAT-reactive neurons in the MS/vDB was not correlated with either hippocampal cholinergic markers. This might be attributed to different collateralization of cholinergic neurons or to different projections of these neurons to other brain regions. These results show a strong hereditary variability within the septo-hippocampal cholinergic system in mice. In view of the role of the cholinergic system in learning and memory processes, strain differences in cholinergic markers might be helpful in explaining behavioral variation.
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PMID:Genetic variation in the morphology of the septo-hippocampal cholinergic and GABAergic system in mice. I. Cholinergic and GABAergic markers. 879 15

Behavioral abnormalities, jumping reaction, increase in spontaneous activity abnormal violence, and lethargy were observed in long-term ultraviolet A (UVA)-irradiated hairy male Crj:CD-1 mice. The learning ability of 6- and 12-months UVA-irradiated mice was significantly reduced compared to un-irradiated age-matched mice. Acetylcholine levels, acetylcholinesterase and choline acetyltransferase activities in the whole brains were decreased in both of 6- and 12-month irradiated mice. Only 1 of 6 mice irradiated for 12 months was histologically observed to have a drastic loss of bilateral hippocampal pyramidal cells in the CA1 field of Ammon's horn.
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PMID:Abnormalities in behavior, learning ability, and the cholinergic system induced by long-term ultraviolet A irradiation of mice. 884 Mar 40

This study compared the morphological characteristics and the behavioural effects of intrahippocampal septal cell suspension grafts injected either just above the pyramidal cell layer of the hippocampal region CA1 or within the dorsal leaf of the dentate gyrus (DG) in rats subjected to electrolytic fimbria-fornix lesions. The behavioural tests determined home-cage and open-field activity, as well as radial-maze performance. Cresyl-violet staining, acetylcholinesterase (AChE) histochemistry, and parvalbumin, glial fibrillary acidic protein and glutamic acid decarboxylase immunocytochemistry were used for morphological assessments. The cross-sectional area of the grafts was measured between 0.8 mm and 5.3 mm posterior to Bregma and used as an index of their development. Whether injected into CA1 or DG, the grafts provided the partially denervated hippocampus with a dense AChE-positive reinnervation. Both types of grafts were devoid of reactive astrocytes (although reactive astrocytes were found close to the graft-host interface), contained almost no parvalbumin-positive neurons and showed a high density of GAD-positive terminals. One of the main differences between the two groups of grafted rats was that the suspension injected into the DG yielded grafts that, in the vicinity of the injection sites (between 2.3 mm and 4.3 mm posterior to Bregma), had a cross-sectional area exceeding that of the grafts placed into CA1 by about 63-110% (average 79%), the latter being more dispersed than the former in the coronal plane. In addition, rats with grafts in the DG exhibited granule cell degeneration in the vicinity of the injection sites, whereas rats with grafts in region CA1 showed no damage near the injection sites. Concerning the behavioural data, we found that fimbria-fornix lesions induced hyperactivity in both the home cage and the open field and impaired radial-maze performance. Compared with the lesion-only rats, the grafted rats in both groups had further increased open-field and home-cage activity. While the grafts placed into region CA1 slightly, but significantly, accentuated the lesion-induced deficit in radial-maze performance, those placed into the DG had no effect. These results suggest that intrahippocampal grafts may, in some (still unspecified) conditions, produce adverse behavioural effects or no behavioural effects, despite an acceptable graft-induced cholinergic reinnervation of the hippocampus. They do not allow a clear answer to the question of whether intra-DG and intra-CA1 septal suspension grafts exhibiting almost comparable morphological features (except in their size and their dispersion in the vicinity of the injection sites) induce behavioural effects that would depend on intrahippocampal location of the grafts. They suggest, however, that the granule cell degeneration caused by the implantation procedure, in conjunction with the intragyral development of the graft, probably does not account for some of the reported adverse behavioural effects of intrahippocampal basal forebrain grafts. Finally, the finding that septal cell suspensions placed into the DG yielded larger grafts than when an equivalent number of cells was injected into CA1 might be explained by a larger lesion-induced neurotrophic activity in DG than in region CA1, although both regions had undergone a similar degree of cholinergic denervation.
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PMID:A comparison of behavioural effects and morphological features of grafts rich in cholinergic neurons placed in two sites of the denervated rat hippocampus. 889 50

The hippocampus receives major afferent innervation from the septum. Using organotypic slice culture, we investigated whether coculture with the septum would modulate transmission and plasticity of hippocampal synapses. In septo-hippocampal cocultures, acetylcholinesterase-positive fibers extending from septal tissue to hippocampal slice were observed. Septo-hippocampal cocultures exhibited larger magnitude of long-term potentiation (LTP) in CA3 and CA1 synapses than hippocampal slices cultured alone, without significant changes in maximal synaptic responses and macroscopic hippocampal cytoarchitecture. Unexpectedly, the facilitatory effect on hippocampal LTP was independent of afferent innervation from the septum, because (1) electrical stimulation of the cocultured septum suppressed the induction of hippocampal LTP, (2) chronic application of 1 microM atropine did not block the facilitatory effect, and (3) septo-hippocampal cocultures without contact with each other still showed a larger magnitude of LTP than hippocampal slices alone. These results suggest that diffusible factor(s) released from the septal tissue modulate functional maturation of hippocampal synapses as to the ability to support synaptic plasticity.
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PMID:Effects of coculture with the septum on the expression of long-term potentiation in organotypic hippocampal slice cultures. 900 76

Ovarian steroids have many effects on the brain throughout the lifespan, beginning during gestation and continuing into senescence. These hormones affect areas of the brain that are not primarily involved in reproduction, such as the basal forebrain, hippocampus, caudate putamen, midbrain raphe, and brainstem locus coeruleus. Here we discuss three effects of estrogens and progestins that are especially relevant to memory processes and identify hormonal alterations associated with aging and neurodegenerative diseases. First, estrogens and progestins regulate synaptogenesis in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estradiol and involves N-methyl-D-aspartate (NMDA) receptors, whereas synaptic downregulation involves intracellular progestin receptors. Second, there are developmentally programmed sex differences in the hippocampal structure that mat help explain why male and female rats use different strategies to solve spatial navigation problems. During the period of development when testosterone is elevated in the male, aromatase and estrogen receptors are transiently expressed in the hippocampus. Recent data on behavior and synapse induction strongly suggest that this pathway is involved in the masculinization or defeminization of hippocampal structure and function. Third, ovarian steroids have effects throughout the brain, including effects on brainstem and midbrain catecholaminergic neurons, midbrain serotonergic pathways, and the basal forebrain cholinergic system. Regulation of the serotonergic system appears to be linked to the presence of estrogen- and progestin-sensitive neurons in the midbrain raphe, whereas the ovarian steroid influence on cholinergic function involves induction of choline acetyltransferase and acetylcholinesterase according to a sexually dimorphic pattern. Because of these widespread influences on these various neuronal systems, it is not surprising that ovarian steroids produce measurable cognitive effects after ovariectomy and during aging.
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PMID:Ovarian steroids and the brain: implications for cognition and aging. 915 61

1. Intracellular current clamp recordings were made from CA1 pyramidal neurones in rat hippocampal slices. Experiments were performed in the presence of ionotropic glutamate receptor antagonists and gamma-aminobutyric acid (GABA) receptor antagonists to block all fast excitatory and inhibitory synaptic transmission. A single stimulus, delivered extracellularly in the stratum oriens, caused a reduction in spike frequency adaptation in response to a depolarizing current step delivered 2 s after the stimulus. A 2- to 10-fold increase in stimulus intensity evoked a slow excitatory postsynaptic potential (EPSP) which was associated with a small increase in input resistance. The peak amplitude of the EPSP occurred approximately 2.5 s after the stimulus and its magnitude (up to 30 mV) and duration (10-50 s) increased with increasing stimulus intensity. 2. The slow EPSP was unaffected by the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG; 1000 microM) but was greatly enhanced by the acetylcholinesterase inhibitor physostigmine (1-5 microM). Both the slow EPSP and the stimulus-evoked reduction in spike frequency adaptation were inhibited by the muscarinic acetylcholine receptor (mAChR) antagonist atropine (1-5 microM). These results are consistent with these effects being mediated by mAChRs. 3. Both the mAChR-mediated EPSP (EPSPm) and the associated reduction in spike frequency adaptation were reversibly depressed (up to 97%) by either adenosine (100 microM) or its non-hydrolysable analogue 2-chloroadenosine (CADO; 0.1-5.0 microM). These effects were often accompanied by postsynaptic hyperpolarization (up to 8 mV) and a reduction in input resistance (up to 11%). The selective adenosine A1 receptor agonists 2-chloro-N6-cyclopentyladenosine (CCPA; 0.1-0.4 microM) and R(-)N6-(2-phenylisopropyl)-adenosine (R-PIA; 1 microM) both depressed the EPSPm. In contrast, the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 0.5-1.0 microM) did not significantly affect the EPSPm. 4. The selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 microM) fully reversed the depressant effects of both adenosine (100 microM) and CADO (1 microM) on the EPSPm and the stimulus-evoked reductions in spike frequency adaptation. 5. DPCPX (0.2 microM) alone caused a small but variable mean increase in the EPSPm of 22 +/- 19% and enabled activation of an EPSPm by a previously subthreshold stimulus. In contrast, the selective adenosine kinase inhibitor 5-iodotubercidin (5-IT; 10 microM) inhibited the EPSPm by 74 +/- 10%, an effect that was reversed by DPCPX. 6. The concentration-response relationship for the depressant action of CADO on the EPSPm more closely paralleled that for its presynaptic depressant action on glutamate-mediated EPSPs than that for postsynaptic hyperpolarization. The respective mean IC50 and EC50 concentrations for these effects were 0.3, 0.8 and 3.0 microM. 7. CADO (1-5 microM) did not have a significant effect on the postsynaptic depolarization, increase in input resistance and reduction in spike frequency adaptation evoked by carbachol (0.5-3.0 microM). All these effects were abolished by atropine (1 microM). 8. These data provide good evidence for an adenosine A1 receptor-mediated inhibition of mAChR-mediated synaptic responses in hippocampal CA1 pyramidal neurones. This inhibition is mediated predominantly presynaptically, is active tonically and can be enhanced when extracellular levels of endogenous adenosine are raised.
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PMID:Regulation of muscarinic acetylcholine receptor-mediated synaptic responses by adenosine receptors in the rat hippocampus. 923 98

The present experiments were designed to elucidate the time frame in which an evoked cholinergic impulse decreases the Ca2+-dependent K+ current (IsAHP) in hippocampal CA1 neurons, and to determine to what extent acetylcholinesterase (AChE) inhibitors enhance the efficacy of the cholinergic impulse. Whole cell voltage-clamp recordings were performed on hippocampal CA1 neurons of rat brain slices and IsAHPs were evoked by constant depolarizing pulses. Cholinergic afferent fibers in stratum oriens were stimulated electrically and the time interval between the afferent stimulus and the depolarizing pulse was varied from 1 to 30 s. In slices perfused with the standard external medium, the afferent stimulus caused a profound decrease in the following IsAHP only when the stimulus preceded the depolarizing pulse by 1-2 s. The stimulus was without effects on the IsAHP when applied >/=5s before the depolarizing pulse. The effects of the afferent stimulus were greatly enhanced in CA1 neurons exposed to the catalytic AChE inhibitors neostigmine, physostigmine, or 9-amino-1,2,3, 4-tetrahydro-acridine. A substantial decrease in the IsAHP was observed even when the stimulus preceded the depolarizing pulse by >/=30 s. However applications of peripheral site AChE inhibitors decamethonium and propidium caused only minor or no enhancement of the IsAHP reduction after the afferent stimulus. We suggest in physiological conditions that muscarinic modulation of ionic conductances of CNS neurons has a limited time course after a cholinergic impulse and that the modulation is greatly enhanced and prolonged when catalytic activities of AChEs are suppressed pharmacologically.
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PMID:Kinetics of muscarinic reduction of IsAHP in hippocampal neurons: effects of acetylcholinesterase inhibitors. 940 19

The septo-hippocampal pathway contains a major gamma-aminobutyric acid (GABA) projection to dendritic fields within the hippocampus. To determine the importance of the septo-hippocampal pathway in ischemia-induced accumulation of GABA and subsequent cell death in area CA1 of hippocampus, septo-hippocampal deafferentation of adult gerbils was performed. Electrolytic lesions were produced in the medial or medial plus lateral septal regions in gerbils 7 days prior to being subjected to 5 min forebrain ischemia. The extent of deafferentation of the dorsal hippocampus was determined histochemically by acetylcholinesterase staining. Both the medial and medial plus lateral septal lesions produced nearly complete loss of acetylcholinesterase staining in the dorsal hippocampus indicating relatively complete deafferentation. During and following ischemia, in vivo microdialysis was used to measure extracellular GABA accumulation, which reached concentrations up to 1060 +/- 143% of basal. Septo-hippocampal deafferentation in both groups of lesioned animals failed to prevent the accumulation of GABA (and glutamate) induced by ischemia, indicating that ischemia-induced GABA accumulation in area CA1 arises principally from intrinsic GABAergic interneurons. Ischemic animals with medial septal lesions did not demonstrate neuroprotection or increased damage in the stratum pyramidale 7 days after reperfusion. Since the septo-hippocampal pathway provides the source of GABAergic disinhibition within the hippocampus, neither disinhibition nor the septo-hippocampal input appear to play an important role in the development of ischemia-induced neuronal death in the hippocampus.
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PMID:Ischemic injury and extracellular amino acid accumulation in hippocampal area CA1 are not dependent upon an intact septo-hippocampal pathway. 951 50

Various animal models, involving different brain insults, lead to memory deficits, which can be measured using behavioral tests. In numerous studies, using five different experimental models in rats, we have found that cognitive dysfunction is invariably accompanied by hippocampal CA1 and CA3 pyramidal cells degeneration. However, of these two, the most affected area changes from one model to the other. The present manuscript describes and compares the morphological alterations within the hippocampus in the following experimental models: normal aging, hypoxia, prolonged corticosterone administration, brain ischemia and cholinesterase (ChE) inhibition. In all the above, many hippocampal neurons were severely damaged, however, CA3 pyramidal cells were mostly affected in normal aging and following hypobaric hypoxia, whereas CA1 cells were especially affected following corticosterone administration, global ischemia and ChE inhibition. Several mechanisms, which might be involved in the diverse courses of the lesions are being considered: cerebral oxygen and glucose, glutamate neurotoxicity and calcium involvement. It is anticipated that elucidation of the specific role of CA1 and CA3 hippocampal sub-fields in the various experimental models might help in understanding processes such as age-related neuronal degeneration and assist in their prevention.
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PMID:Sub-regional hippocampal vulnerability in various animal models leading to cognitive dysfunction. 986 31


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