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At least 595 records · Page 33Linked to original sources

PubMed1997

Altered glutamatergic transmission in neurological disorders: from high extracellular glutamate to excessive synaptic efficacy.

This review is a critical appraisal of the widespread assumption that high extracellular glutamate, resulting from enhanced pre-synaptic release superimposed on deficient uptake and/or cytosolic efflux, is the key to excessive glutamate-mediated excitation in neurological disorders. Indeed, high extracellular glutamate levels do not consistently correlate with, nor necessarily produce, neuronal dysfunction and death in vivo. Furthermore, we exemplify with spreading depression that the sensitivity of an experimental or pathological event to glutamate receptor antagonists does not imply involvement of high extracellular glutamate levels in the genesis of this event. We propose an extension to the current, oversimplified concept of excitotoxicity associated with neurological disorders, to include alternative abnormalities of glutamatergic transmission which may contribute to the pathology, and lead to excitotoxic injury. These may include the following: (i) increased density of glutamate receptors; (ii) altered ionic selectivity of ionotropic glutamate receptors; (iii) abnormalities in their sensitivity and modulation; (iv) enhancement of glutamate-mediated synaptic efficacy (i.e. a pathological form of long-term potentiation); (v) phenomena such as spreading depression which require activation of glutamate receptors and can be detrimental to the survival of neurons. Such an extension would take into account the diversity of glutamate-receptor-mediated processes, match the complexity of neurological disorders pathogenesis and pathophysiology, and ultimately provide a more elaborate scientific basis for the development of innovative treatments.

Animals↗

PubMed2000

Dysfunctional regulation of alphaCaMKII and syntaxin 1B transcription after induction of LTP in the aged rat.

Syntaxin 1B and alphaCaMKII are two genes that are upregulated after the induction of LTP and appear to underlie different mechanisms of synaptic plasticity. alphaCaMKII is directly implicated in strengthening the synapses that have been modified, whereas syntaxin 1B has been implicated in a mechanism for the propagation of synaptic plasticity within neural circuits. In these experiments we have investigated whether the regulation of these genes is altered after the induction of LTP in aged rats. We found, three hours after the induction of LTP in the dentate gyrus, that aged rats could be subgrouped into those in which LTP was maintained and those in which LTP had decayed back to basal levels. Both genes were upregulated in young adult rats, whereas there was a differential pattern of LTP-induced expression in the aged rats. Dendritic alphaCaMKII was upregulated in aged rats only when LTP was maintained. In contrast, regulation of syntaxin 1B and alphaCaMKII was absent in the granule cell bodies of the aged rats regardless of whether LTP was maintained or not. These results suggest that molecular mechanisms implicated in two aspects of hippocampal synaptic plasticity malfunction during normal ageing and therefore may have some contributory role in the decline in memory function routinely observed in ageing.

Aging↗

PubMed2001

A hypothalamic digoxin mediated model for conscious and subliminal perception.

The isoprenoid pathway and its metabolites--digoxin, dolichol and ubiquinone were assessed in schizophrenia. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in schizophrenia. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead on to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites--serotonin and quinolinic acid (NMDA agonist), and decreased levels of hyperpolarising tyrosine catabolites--dopamine and noradrenaline contributing to membrane Na+-K+ ATPase inhibition. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistance important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging & defective apoptosis leading on to abnormal synaptogenesis. Schizophrenia can thus be considered as a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway.

Adult↗

PubMed2002

Pathophysiology of depression: the concept of synaptic plasticity.

Neuronal plasticity or remodeling is most often discussed with regard to cellular and behavioral models of learning and memory. However, neuronal plasticity is a fundamental process by which the brain acquires information and makes the appropriate adaptive responses in future-related settings. Dysfunction of these fundamental processes could thereby contribute to the pathophysiology of mood disorders, and recovery could occur by induction of the appropriate plasticity or remodeling. These possibilities are supported by preclinical and clinical studies demonstrating that there are structural alterations that occur in response to stress and in patients with mood disorders. Moreover, antidepressant treatment may oppose these effects by regulation of signal transduction and gene expression pathways linked to neuronal plasticity. These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions.

Antidepressive Agents↗

PubMed2002

Early chronic aluminium exposure impairs long-term potentiation and depression to the rat dentate gyrus in vivo.

As an important neurotoxin, aluminium can cause cognitive dysfunctions and mental diseases. Previous studies have reported that aluminium impaired long-term potentiation (LTP) in vivo and in vitro. Here, we utilise two models of synaptic plasticity, LTP and long-term depression (LTD) to study the effects of aluminium on synaptic plasticity in vivo. Neonatal Wistar rats were chronically exposed to aluminium from birth to weaning via the milk of dams fed with 0.3% aluminium chloride solution. Excitatory postsynaptic potential (EPSP) and population spikes (PS) were recorded from the dentate gyrus (DG) of adult rats by electrically stimulating the perforant path. THE FOLLOWING RESULTS WERE OBTAINED: (1) The input/output function indicated that, as compared to controls, aluminium increased the baseline amplitude of the PS, but decreased the baseline slope of EPSP. (2) Aluminium significantly prevented LTD in PS (controls: 77.36+/-6.7%, n=7; aluminium-exposed: 102.01+/-9.1%, n=7; P<0.05) and decreased the LTD amplitude in EPSP (controls: 76.61+/-4.1%, n=7; aluminium-exposed: 94.31+/-7.9% n=7, P<0.05). (3) Aluminium reduced the amplitude of LTP in both PS (controls: 190+/-16.1%, n=7; aluminium-exposed: 135+/-9.7%, n=7; P<0.05) and EPSP (control: 132+/-9.3%, n=7; aluminium-exposed: 115+/-10.6%, n=7; P<0.05). As for LTD and LTP, PS was impaired more seriously than EPSP in aluminium-exposed rats. (4) Aluminium exposure decreased the paired-pulse facilitation (PPF) of PS at 30-150 ms interpulse interval (IPI), and reduced 93.5% of PPF at 80 ms IPI in PS (controls: 243.4+/-39.8%, n=7; aluminium-exposed: 149.9+/-12.3%, n=7). There was no significant difference in EPSP of PPF. From these results we conclude that aluminium exposure in neonatal rats thus reduces the amplitude of LTP and PPF and blocks the induction of LTD in the DG. We suggest that aluminium affects both presynaptic and postsynaptic mechanisms of synaptic transmission.

Aluminum↗

PubMed1998

Modeling dopamine system dysfunction in experimental animals.

Quite a substantial number of human disorders have been associated with a primary or a secondary impairment of one or several of the dopaminergic pathways. Among disorders associated with a primary impairment of dopaminergic transmission are Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, and possibly schizophrenia. Diseases of secondary dopamine dysfunction are chiefly represented by Huntington's disease in which dopaminergic transmission is being interrupted by progressive loss of the striatal neurons bearing the postsynaptic D1- and D2-dopamine receptors. Central dopaminergic systems have anatomical as well as organizational properties that render them unique by comparison to other neurotransmission systems, making them able to play a pivotal role in the modulation of various important brain functions such as locomotor activity, attention, and some cognitive abilities. These properties of dopamine neurons have obviously several implications in the clinical expression of human disorders involving dopamine neuron dysfunction. In addition, they can greatly influence the clinical/behavioral consequences of experimental lesions in animal models of dopamine dysfunctions.

Animals↗

PubMed2004

Tetanus in pregnancy.

Tetanus remains a leading cause of maternal and neonatal morbidity and mortality in developing countries. It is caused by the release of two toxins produced by Clostridium tetani, a noninvasive gram-positive anaerobic bacillus. Tetanospasmin is taken up by the neuronal end plates and prevents neurotransmitter release at the synaptic junction. This leads to spasms and is irreversible. Recovery requires the formation of new neurons and may take months. Generalized muscle spasm, respiratory compromise, and autonomic dysfunction are all common clinical manifestations. Diagnosis is based mainly on history and clinical examination. The management of the pregnant woman is similar to the nonpregnant individual. The main objectives are prompt prevention of further toxin absorption, wound debridement, antibiotic therapy, and aggressive supportive care. Primary and secondary prevention protocols are important worldwide because tetanus is a preventable disease. The tetanus toxoid vaccine can be given in pregnancy.

Clostridium tetani↗

PubMed2004

Development of neuronal sensitivity to toxins in cerebrospinal fluid from HIV-type 1-infected individuals.

HIV infection of the immature nervous system generally results in a rapid progression of neurological disease that cannot easily be explained by the severity of encephalitis, viral burden, systemic immune deficiency, or developmental changes in utero. Rather than the viral infection dictating disease progression, we explored the possibility that immature neurons might be particularly sensitive to toxins secreted in response to HIV. Primary cultures of rat cortical neurons were exposed to toxic cerebrospinal fluid (CSF) from HIV-infected individuals (CSF(tox)) and evaluated for changes in intracellular calcium and cell death. CSF(tox) had no detectable effect on early neurite outgrowth, calcium regulation, or cell death during the first few days in culture. Starting at Day 4, delayed increases in intracellular calcium appeared in response to CSF(tox). The magnitude of the delayed calcium rise and cell death increased with the age of the culture and correlated with the appearance of synaptophysin immunoreactive varicosities. A similar gradual development of sensitivity was seen during exposure of feline neurons to toxins generated by choroid plexus macrophages after exposure to feline immunodeficiency virus. The possibility that toxin sensitivity is dependent on the presence of synaptic activity is consistent with the rapid pathogenesis in the CNS seen during the first postnatal year. Emerging synaptic activity coupled with other factors such as high metabolic demand in the young nervous system may combine to increase the likelihood of calcium overload and neuronal dysfunction in response to HIV-associated toxins.

Animals↗

PubMed1990

Neurophysiological observations on corticospinal projections to the upper limb in subjects with Rett syndrome.

The aim of the present study was to investigate the excitability of corticospinal neurons and the integrity of their projections to the alpha motor neurons through the corticospinal tract in subjects of different ages with Rett syndrome. Electromagnetic stimulation of the motor cortex and cervical motor roots was used to evoke motor action potentials in the biceps brachii and hypothenar muscles. The phasic stretch reflex in the biceps brachii was also recorded to study the excitability of spinal alpha motor neurons. Motor cortex stimulation evoked motor action potentials at low threshold and with abnormally short latencies and prolonged durations. In contrast cervical motor root stimulation resulted in responses of normal latency and duration. The phasic stretch reflex had a low threshold, short latency and prolonged duration. It is concluded that in Rett syndrome the corticospinal pathway is intact. The results suggest disordered synaptic control of the Betz cell of the motor cortex and/or the spinal alpha motor neuron, although the involvement of the latter might be a consequence of dysfunction in supraspinal descending motor pathways.

Adolescent↗

PubMed2006

Current pharmacotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 4.5 million people in the United States. The mainstays of current pharmacotherapy for AD are compounds aimed at increasing the levels of acetylcholine in the brain, thereby facilitating cholinergic neurotransmission through inhibition of the cholinesterases. These drugs, known as acetylcholinesterase inhibitors (AChEIs), were first approved by the U.S. Food and Drug Administration (FDA) in 1995 based on clinical trials showing modest symptomatic benefit on cognitive, behavioral, and global measures. In 2004 the FDA approved memantine, an NMDA antagonist, for treating dementia symptoms in moderate to severe AD cases. In clinical practice, memantine may be co-administered with an AChEI, although neither drug individually or in combination affects the underlying pathophysiology of dementia. Dementia in AD results from progressive synaptic loss and neuronal death. As knowledge of the mechanisms responsible for neurodegeneration in AD increases, it is anticipated that neuroprotective drugs to slow or prevent neuronal dysfunction and death will be developed to complement current symptomatic treatments.

Alzheimer Disease↗

PubMed2005

Mechanisms of late-onset cognitive decline after early-life stress.

Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of "acquired" contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life "psychological" stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period. At the cellular level, disturbances to hippocampal long-term potentiation paralleled the behavioral changes and were accompanied by dendritic atrophy and mossy fiber expansion. These findings constitute the first evidence that a short period of stress early in life can lead to delayed, progressive impairments of synaptic and behavioral measures of hippocampal function, with potential implications to the basis of age-related cognitive disorders in humans.

Age Factors↗

PubMed2003

Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory.

Amyloid-beta precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-beta (Abeta) peptide found in neuritic plaques of Alzheimer's disease (AD) patients. Because Abeta shows neurotoxic properties, and because familial forms of AD promote Abeta accumulation, a massive international research effort has been aimed at understanding the mechanisms of Abeta generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPalpha (sAPPalpha), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Abeta appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Abeta, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Abeta, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease.

Alzheimer Disease↗

PubMed1999

Acceleration of ageing-related gliopathic changes and hippocampal dysfunction following intracerebroventricular infusion of cysteamine in adult rats.

The sulphydryl agent, cysteamine, accelerates the ageing-related accumulation of peroxidase-positive (iron-rich) cytoplasmic inclusions in rat subcortical astroglia and induces their appearance in primary neuroglial cultures. In the present study, infusion of cysteamine into the lateral ventricle of young, adult rats (1 mg/day for three weeks followed by a one-month drug "washout" period) significantly increased numbers of peroxidase-positive astrocytic granules in the stratum oriens of the CA1 hippocampus relative to saline-infused controls. In contrast to the gliopathic changes, no evidence of neuronal or myelin damage was observed in the cysteamine-exposed rats. The cysteamine-treated animals exhibited significant impairment in spatial learning as determined using a three-panel runway task. The working memory deficits were more robust at the end of the drug washout period than immediately following cessation of the cysteamine infusion. Thus, the cysteamine-related memory deficits are of long duration and are not due to any acute neuroactive properties of the drug itself. Using hippocampal slices prepared after the drug washout period, we observed attenuated paired-pulse depression, with no significant effects on basal excitatory synaptic transmission or induction of long-term potentiation, in the cysteamine-infused animals relative to controls. We propose that, in cysteamine-treated rats and in the course of normal ageing, hippocampal dysfunction and associated cognitive deficits may be secondary to fundamental pathological processes originating within the astroglial compartment.

Aging↗

PubMed1998

Aging and oxidative stress in neurodegeneration.

The effect of oxidative stress on the function of brain synapse, the difference in susceptibility of synapse to hyperoxia with age, and the changes in vitamin E status by stress and aging were investigated. Synaptic membrane permeability to sucrose was increased with age. When rats were subjected to hyperoxia, the membrane permeability on each age increased significantly. The susceptibility of synapse of 25 month old rats exposed to stress was about 2.5 times higher than unexposed old rats. The synaptic plasma membrane fluidity decreased significantly either in response to hyperoxia or during aging. The thiobarbituric acid reactive substances (TBARS) in the synaptic plasma membranes increased with age, and those in the membranes of oxygen-exposed rats were higher than in the unexposed rats. The cholesterol/phospholipids (C/P) ratio of the membranes increased significantly with age, and the values in the membranes of oxygen-exposed rats increased more significantly than in unexposed rats of each age. In a measurement of fatty acid content in the membranes, the content of docosahexaenoic acid (DHA, C22:6) decreased significantly during aging and by hyperoxia. These results suggest that free radicals derived from oxygen may attack nerve terminals and peroxidize the membrane, resulting in the deterioration of function of brain synapse, and that susceptibility of synapse to oxidative stress was significantly increased with age. Vitamin E content in the synaptic plasma membranes decreased with age. When rats were subjected to oxidative stress, the content was lower in each age than in normal rat membranes. An intraperitoneal administration of vitamin E prior to stress reduced these abnormalities. It is obvious that vitamin E contributes to the protection against nerve terminal dysfunction caused by oxidative stress.

Aging↗

PubMed1995

Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis.

Structural change in the hippocampal formation has become popular as a proposed neurobiological substrate for schizophrenic disorders. It is postulated that behavioral plasticity in the form of long-term potentiation of hippocampal synaptic transmission is an attractive putative mechanism for the mediation of transient psychosis. Moreover, the disturbed hippocampal neuroarchitecture found in schizophrenic brain may be susceptible to potentiation and dysfunctional to the degree that delusions and hallucinations develop. Partial and selective blockade of the receptors mediating potentiation may prove to be an efficient means of preventing psychotic episodes and avoiding further damage to the involved network. Basic research, utilizing experimental models such as intraventricular kainic acid injection, may help to clarify the anatomical and physiological substrate of psychosis.

Arousal↗

PubMed2006

Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of beta-amyloid (Abeta)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Abeta42/Abeta40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximately 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.

Aging↗

PubMed2006

An association study between catechol-O-methyl transferase gene polymorphism and methamphetamine psychotic disorder.

OBJECTIVE: A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. BASIC METHODS: We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. MAIN RESULTS: We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. CONCLUSIONS: Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Adult↗

PubMed1991

Sensitivity to curare in patients with upper and lower motor neurone dysfunction.

Sensitivity to the action of nondepolarising relaxants was compared in muscles of upper and lower limbs in four syringomyelic patients undergoing elective neurosurgical procedures. It was observed that muscles with signs of lower motor neurone dysfunction are supersensitive to the action of nondepolarising relaxants. Terminal sprouting of motor axons and the occurrence of newly formed neuromuscular junctions may be responsible for a low synaptic efficacy and may explain the high sensitivity to factors that reduce the safety margin of neuromuscular transmission.

Adult↗