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At least 613 records · Page 34Linked to original sources
PubMed1991

[Auto-cholinergic synapse dysfunction in patients with generalized epileptic seizures. A preliminary report].

The mechanism of epileptic seizures so far remains unclear. Immunological disturbances may be one of the possible mechanisms. The assumption that primary epilepsy is an autoimmune disease lacks an experimental basis. In order to search any relationship between generalized epileptic seizures and autoimmune we examined and measured the serum anti-acetylcholine receptor antibody (A AchR Ab) and anti-synaptic premembrane antibody (A PrM Ab) in 12 patients with typical absences, 20 patients with generalized tonic-clonic seizures (GTC) and 6 patients with Lennox-Gastaut Syndrome. 2 (16.7%) out of 12 patients with absences showed positive both A AchR Ab and A PrM Ab, positive A AchR Ab in 1 patient. Among 20 patients with GTC both A AchR Ab and A PrM Ab were positive in 7 patients (35%), A PrM Ab was positive in 1 patient. Totally in 8 patients A PrM Ab was positive. However, the difference between the two Antibodies was not significant (1.1:1). The two kinds of antibody were positive in 5 (83%) out of 6 patients and A PrM Ab was positive, but A AchR Ab was doubtful in another one patient with Lennox-Gastaut syndrome. Therefore, all the patients with Lennox-Gastaut syndrome showed positive antibody. Our data suggested that different types of generalized epileptic-seizures showed different severity of autoimmune dysfunction. The meaning of this kind of immune dysfunction needs further investigation.

Adolescent↗
PubMed2003

Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice.

A critical question in Alzheimer's disease (AD) research is the cause of memory loss that leads to dementia. The amyloid precursor protein + presenilin-1 (APP+PS1) transgenic mouse is a model for amyloid deposition, and like AD, the mice develop memory deficits as amyloid deposits accumulate. We profiled gene expression in these transgenic mice by microarray and quantitative RT-PCR (qRT-PCR). At the age when these animals developed cognitive dysfunction, they had reduced mRNA expression of several genes essential for long-term potentiation and memory formation (Arc, Zif268, NR2B, GluR1, Homer-1a, Nur77/TR3). These changes appeared to be related to amyloid deposition, because mRNA expression was unchanged in the regions that did not accumulate amyloid. Transgene expression was similar in both amyloid-containing and amyloid-free regions of the brain. Interestingly, these changes occurred without apparent changes in synaptic structure, because a number of presynaptic marker mRNAs (growth-associated protein-43, synapsin, synaptophysin, synaptopodin, synaptotagmin, syntaxin) remained stable. Additionally, a number of genes related to inflammation were elevated in transgenic mice, primarily in the regions containing amyloid. In AD cortical tissue, the same memory-associated genes were downregulated. However, all synaptic and neuronal transcripts were reduced, implying that the loss of neurons and synapses contributed to these changes. We conclude that reduced expression of selected genes associated with memory consolidation are linked to memory loss in both circumstances. This suggests that the memory loss in APP+PS1 transgenic mice may model the early memory dysfunction in AD before the degeneration of synapses and neurons.

Aged↗
PubMed2003

A hypothalamic digoxin-mediated model for autism.

The isoprenoid pathway and its metabolites--digoxin, dolichol, and ubiquinone--were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. 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 autism. 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 to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites--serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites--dopamine, noradrenaline, and morphine--contributing to membrane Na+-K+ ATPase inhibition. Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. 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 persistence 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 and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism.

Adolescent↗
PubMed1986

Alpha-adrenergic mechanisms in the pathophysiology of left ventricular heart failure--an analysis of their role in systolic and diastolic dysfunction.

Alpha-adrenoceptor (alpha-AR) mechanisms may contribute to systolic and diastolic dysfunction of the left ventricle. Centrally acting alpha 2-AR agonist drugs, including methyldopa, clonidine, and guanabenz, activate brainstem alpha 2-AR and this activation results in a decrease in overall sympathetic tone and an increase in parasympathetic tone. Peripherally acting alpha 1-AR antagonists, such as prazosin, inhibit the actions of catecholamines at post-synaptic receptor sites. Heart failure is characterized by hyperactivity of sympathetic pathways and parasympathetic withdrawal. In this situation, alpha 2-agonists reduce sympathetic activity and improve hemodynamic parameters of cardiac function; both acute and chronic administration of alpha 2-AR have been demonstrated to reduce serum catecholamine levels, heart rate, and arterial blood pressure, and to improve exercise performance. Diastolic dysfunction of the left ventricle is characterized by a marked decrease in ventricular compliance, often a result of hypertension and left ventricular hypertrophy; the end result is an increase in left ventricular filling pressure and pulmonary venous pressure. Treatment with alpha 2-AR, by decreasing sympathetic tone and blood pressure, and alpha 1-AR antagonists, by reducing blood pressure and by directly inhibiting the actions of catecholamines at alpha 1-AR, may produce a reduction in the degree of ventricular hypertrophy and improve diastolic performance of the left ventricle. Thus, therapeutic intervention in heart failure with either alpha 2-AR agonists or alpha 1-AR antagonists may favorably modulate these alterations in sympathetic tone and improve ventricular function.

Adrenergic alpha-Antagonists↗
PubMed2004

Glutamate transporters: animal models to neurologic disease.

Glutamate is the primary excitatory amino acid neurotransmitter in the central nervous system and its activity is carefully modulated in the synaptic cleft by glutamate transporters. A number of glutamate transporters have been identified in the central nervous system and each has a unique physiologic property and distribution. Glutamate transporter dysfunction may either be an initiating event or part of a cascade leading to cellular dysfunction and ultimately cell death. Animal models of glutamate transporter dysfunction have revealed a significant role for these proteins in pathologic conditions such as neurodegenerative diseases, epilepsy, stroke, and central nervous system tumors. Recent work has focused on glutamate transporter biology in human diseases with an emphasis on how manipulation of these transporter proteins may lead to therapeutic interventions in neurologic disease.

Amino Acid Transport System X-AG↗
PubMed1998

Manipulation of NMDA-receptor activity alters extinction of an instrumental response in rats.

The effects of pharmacologically manipulating N-methyl-D-aspartate(NMDA)-receptor activity were examined during extinction of an appetitive instrumental response in rats. After reaching acquisition criterion, subjects were treated with the antagonist dizocilpine maleate (MK801; 0.1 mg/kg), the agonist D-cycloserine (3 mg/kg), or vehicle-alone (control) and tested during a non-reinforced (extinction) session. The antagonist decreased the average number of responses occurring during the test session whereas the agonist increased the average number in contrast to controls. The effect on retention performance may be mediated by differential influence on the N-methyl-D-aspartate-dependent synaptic plasticity that occurs during associative learning. In conjunction with other studies, these data suggest that N-methyl-D-aspartate agonism may be an effective intervention for memory dysfunction.

Animals↗
PubMed2004

Serotonin brain circuits with a focus on hepatic encephalopathy.

Despite enormous strides in our understanding of human disease, the precise mechanisms of hepatic encephalopathy (HE), a potential long-term complication of liver failure, are still unclear. Brain serotonin, a neurotransmitter with widespread distribution in the CNS, plays a role in the regulation of a wide range of physiological behaviors and functions. In addition, it has been implicated in the pathogenesis of several pathological processes, including HE. This work reviews the relationship between brain serotonergic dysfunction and hepatic encephalopathy in cirrhotic patients and experimental animals. The existing changes in the synthesis, metabolism, storage, and release of neuronal serotonin in HE point to a serotonergic synaptic deficit in this condition. Given the established role of the brain serotonergic system in the regulation of sleep, circadian rhythmicity, and locomotion, selective alterations of this system could be an important part of the neurophysiological background responsible for the behavioral changes in rats with portacaval anastomosis and may contribute to the pathogenesis of HE in cirrhotic patients. The findings that serotoninergic turnover is exquisitely and selectively sensitive to the degree of porto-systemic shunting and hyperammonemia suggest a role for serotonin in early neuropsychiatric symptoms of HE. Pharmacological manipulation of the brain serotonergic system may be beneficial in the prevention and treatment of HE in cirrhotic patients.

Animals↗
PubMed2003

Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice.

One hypothesis for the etiology of behavioral disorders is that infection by a virus induces neuronal cell dysfunctions resulting in a wide range of behavioral abnormalities. However, a direct linkage between viral infections and neurobehavioral disturbances associated with human psychiatric disorders has not been identified. Here, we show that transgenic mice expressing the phosphoprotein (P) of Borna disease virus (BDV) in glial cells develop behavioral abnormalities, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit. We demonstrate that the transgenic brains exhibit a significant reduction in brain-derived neurotrophic factor and serotonin receptor expression, as well as a marked decrease in synaptic density. These results demonstrate that glial expression of BDV P leads to behavioral and neurobiological disturbances resembling those in BDV-infected animals. Furthermore, the lack of reactive astrocytosis and neuronal degeneration in the brains indicates that P can directly induce glial cell dysfunction and also suggests that the transgenic mice may exhibit neuropathological and neurophysiological abnormalities resembling those of psychiatric patients. Our results provide a new insight to explore the relationship between viral infections and neurobehavioral disorders.

Animals↗
PubMed2000

Gene expression of PSD95 in prefrontal cortex and hippocampus in schizophrenia.

A number of studies have suggested that disturbance in glutamatergic transmission in the cerebral cortex may underlie, or contribute to the pathophysiology of schizophrenia. In this study we examined expression of the postsynaptic density protein 95 (PSD95) mRNA in the prefrontal cortex and hippocampus in postmortem material from neuroleptic-treated schizophrenics and normal controls. PSD95 is known to bind to NMDA receptor subunits and is known to be involved in synaptic plasticity. In situ hybridization analysis showed that the expression of PSD95 was significantly decreased in Brodmann area 9 of the prefrontal cortex but not in the hippocampus. These results further implicate the prefrontal cortex in the pathophysiology of schizophrenia and suggest dysfunction of NMDA receptors in the schizophrenic cortex.

Aged↗
PubMed2000

Roles of nuclear factor kappaB in neuronal survival and plasticity.

The transcription factor nuclear factor kappaB (NF-kappaB) is moving to the forefront of the fields of apoptosis and neuronal plasticity because of recent findings showing that activation of NF-kappaB prevents neuronal apoptosis in various cell culture and in vivo models and because NF-kappaB is activated in association with synaptic plasticity. Activation of NF-kappaB was first shown to mediate antiapoptotic actions of tumor necrosis factor in cultured neurons and was subsequently shown to prevent death of various nonneuronal cells. NF-kappaB is activated by several cytokines and neurotrophic factors and in response to various cell stressors. Oxidative stress and elevation of intracellular calcium levels are particularly important inducers of NF-kappaB activation. Activation of NF-kappaB can interrupt apoptotic biochemical cascades at relatively early steps, before mitochondrial dysfunction and oxyradical production. Gene targets for NF-kappaB that may mediate its antiapoptotic actions include the antioxidant enzyme manganese superoxide dismutase, members of the inhibitor of apoptosis family of proteins, and the calcium-binding protein calbindin D28k. NF-kappaB is activated by synaptic activity and may play important roles in the process of learning and memory. The available data identify NF-kappaB as an important regulator of evolutionarily conserved biochemical and molecular cascades designed to prevent cell death and promote neuronal plasticity. Because NF-kappaB may play roles in a range of neurological disorders that involve neuronal degeneration and/or perturbed synaptic function, pharmacological and genetic manipulations of NF-kappaB signaling are being developed that may prove valuable in treating disorders ranging from Alzheimer's disease to schizophrenia.

Animals↗
PubMed2003

Cycles of aberrant synaptic sprouting and neurodegeneration in Alzheimer's and dementia with Lewy bodies.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative disorders affecting the elderly. The cognitive and motor deficits in these diseases are associated with the disruption of neuritic substructure, loss of synaptic contacts in selectively vulnerable circuitries, and aberrant sprouting. Where as in AD, accumulation of misfolded forms of Abeta triggers neurodegeneration, in DLB accumulation of alpha-synuclein might play a central role. The mechanisms by which oligomeric forms of these proteins might lead to cycles of synapse loss and aberrant sprouting are currently under investigation. Several possibilities are being considered, including mitochondrial damage, caspase activation, lysosomal leakage, fragmentation of the Golgi apparatus, interference with synaptic vesicle transport and function, and interference with gene transcription and signaling. Among them, recent lines of research support the possibility that alterations in signaling pathways such extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 relevant to synaptic plasticity and cell survival might play a pivotal role. A wide range of cellular functions are affected by the accumulation of misfolded Abeta and alpha-synuclein; thus it is possible that a more fundamental cellular alteration may underlie the mechanisms of synaptic pathology in these disorders. Among them, one possibility is that scaffold proteins, such as caveolin and JNK-interacting protein (JIP), which are necessary to integrate signaling pathways, are affected, leading to cycles of synapse loss and aberrant sprouting. This is significant because both caveolar dysfunction and altered axonal plasticity might be universally important in the pathogenesis of various neurodegenerative disorders, and therefore these signaling pathways might be common therapeutic targets for these devastating diseases.

Alzheimer Disease↗
PubMed2004

Prefrontal cortical projections to the rat dorsal raphe nucleus: ultrastructural features and associations with serotonin and gamma-aminobutyric acid neurons.

Studies of human brain indicate that both the ventromedial prefrontal cortex (PFC) and the dorsal raphe nucleus (DRN) may be dysfunctional in major depressive illness, making it important to understand the functional interactions between these brain regions. Anatomical studies have shown that the PFC projects to the DRN, although the synaptic targets of this excitatory pathway have not yet been identified. Electrophysiological investigations in the rat DRN report that most serotonin neurons are inhibited by electrical stimulation of the PFC, suggesting that this pathway is more likely to synapse onto neighboring gamma-aminobutyric acid (GABA) neurons than onto serotonin cells. We tested this hypothesis by electron microscopic examination of DRN sections dually labeled for biotin dextran amine anterogradely transported from the PFC and immunogold-silver labeling for tryptophan hydroxylase (TrH) or for GABA. In the DRN, the majority of PFC axons either synapsed onto unlabeled dendrites or failed to form detectable synapses in single sections. Other PFC axons synapsed onto either TrH- or GABA-immunolabeled processes. Considerably more tissue sampling was necessary to detect PFC synapses onto TrH- than onto GABA-labeled dendrites, suggesting that the latter connections are more common. In other cases, PFC terminals and TrH- or GABA-immunoreactive dendrites either were closely apposed, without forming detectable synapses, or were separated by glial processes. These results provide potential anatomical substrates whereby the PFC can both directly and indirectly regulate the activity of serotonin neurons in the DRN and possibly contribute to the pathophysiology of depression.

Animals↗
PubMed2003

Huntington's disease: a synaptopathy?

Huntington's disease (HD) is caused by a polyglutamine expansion in the protein huntingtin. In its terminal stage, HD is characterized by widespread neuronal death in the neocortex and the striatum. Classically, this neuronal death has been thought to underlie most of the symptoms of the disease. Accumulating evidence suggests, however, that cellular dysfunction is important in the pathogenesis of HD. We propose that specific impairment of the exocytosis and endocytosis machinery contributes to the development of HD. We also suggest that abnormal synaptic transmission underlies the early symptoms of HD and can contribute to the triggering of cell death in later stages of the disease.

Humans↗
PubMed2005

Central suppression of regenerated proprioceptive afferents.

Long after a cut peripheral nerve reinnervates muscle and restores force production in adult cats, the muscle does not respond reflexively to stretch. Motivated by the likelihood that stretch areflexia is related to problems with sensing and controlling limb position after peripheral neuropathies, we sought to determine the underlying mechanism. Electrophysiological and morphological measurements were made in anesthetized rats having one of the nerves to the triceps surae muscles either untreated or cut and immediately rejoined surgically many months earlier. First, it was established that reinnervated muscles failed to generate stretch reflexes, extending observations of areflexia to a second species. Next, multiple elements in the sensorimotor circuit of the stretch reflex were examined in both the PNS and CNS. Encoding of muscle stretch by regenerated proprioceptive afferents was remarkably similar to normal, although we observed some expected abnormalities, e.g., increased length threshold. However, the robust stretch-evoked sensory response that arrived concurrently at the CNS in multiple proprioceptive afferents produced synaptic responses that were either smaller than normal or undetectable. Muscle stretch failed to evoke detectable synaptic responses in 13 of 22 motoneurons, although electrical stimulation generated monosynaptic excitatory postsynaptic potentials that were indistinguishable from normal. The ineffectiveness of muscle stretch was not attributable therefore to dysfunction at synapses made between regenerated Ia afferents and motoneurons. Among multiple candidate mechanisms, we suggest that centrally controlled neural circuits may actively suppress the sensory information encoded by regenerated proprioceptive afferents to prevent recovery of the stretch reflex.

Afferent Pathways↗
PubMedDate not supplied

A review of the electromyographic criteria in sexual performance.

Given that the criteria for sexual performance including males considered normal is not clear in available literature, the authors sought a way to choose standards that would leave no doubts as far competence of performance and neurophysiological integrity in the control of sexual performance. The results found in more than 5,000 electromyographic evaluations on erectile dysfunction were equivalent to the results from a previous research, "The electromyographic gold standard to male sexual capacity", where normal males were evaluated according to the latency period, amplitude and morphology. To classify the results as "The gold standard", we used a selected and accurate method that excluded any doubts about the sexual performance. These men had the installation capacity, maintenance and control of their ejaculation, totally voluntary. The similarity between the clinical picture and the electromyographic events, suggests that the amplitude and the morphology, beyond the latency period, may indicate the quality of neurotransmission.

Alcoholism↗
PubMed2002

[Dendritic spine structures and functions].

Glutamate sensitivities of single dendritic spines were investigated with a two-photon photolysis of a caged-glutamate compound and the patch-clamp method in mouse hippocampal slice preparations. We found that the fast glutamate responses mediated by AMPA receptors were proportional to the volume of the spine head, but the slow responses induced by NMDA receptors displayed only weak correlation with the spine head volume and were independently regulated with the expression of AMPA receptors. This indicates that the strength of synaptic connection is stored as the spine structures, but that its plasticity may be regulated by independent factors. Abnormalities in spine shapes and distributions are commonly detected in most brain dysfunctions, including metal retardations, where structural consolidation phase may be impaired. These observations suggest that a physical basis of the memory in the cerebral cortex resides in the alteration and maintenance of spine structures.

Animals↗
PubMed2001

Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus.

A model for the pathophysiology of depression is discussed in the context of other existing theories. The classic monoamine theory of depression suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. More recent elaborations of the classic theory also implicitly include this postulate, other theories of depression frequently prefer to depart from the monoamine-based model altogether. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity, and concomitantly, exaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to dysregulation of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Concomitant impairments in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptivity to stressful stimuli.

Animals↗