SEARCH · PubMed Health

Results for “synaptic dysfunction”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,027 records · Page 57Linked to original sources

PubMed1976

In defense of SISIs. The short increment sensitivity index.

We review the Short Increment Sensitivity Index (SISI) in terms of its performance with a variety of sites of lesion and its likely physiologic basis. We conclude that its original schema can be broadened to extend its clinical application if changes are made in the parameters of its routine use. The two major changes involve (1) a presentation level of no less than 90 dB hearing threshold level (HTL) and (2) a bimodal interpretation of results based on the premise that high scores indicate normal cochlear function and low scores indicate extensive cochlear damage or neural dysfunction. We suggest that routine use of the modifications suggested here can provide useful diagnostic information and bring to light a group of neurally impaired patients that has been relatively ignored.

Audiometry↗

PubMed1986

Scopolamine impairs learning performance of rats in a 14-unit T-maze.

To assess involvement of muscarinic cholinergic systems in performance of a shock-motivated 14-unit T-maze task, 3-month old Fischer-344 rats were given an IP injection of scopolamine (0.1, 0.3, 1.0 or 3.0 mg/kg), methylscopolamine (1.0 mg/kg), or saline 30 min prior to maze training on 2 consecutive days. Scopolamine, but not methylscopolamine, impaired all components of acquisition performance. Measures of error performance, run time, shock duration, and number of shocks received were significantly increased but only at the 1.0 and 3.0 mg/kg scopolamine doses. The cognitive component of the task, measured by error performance, appeared most affected. Cognitive performance deficits observed following scopolamine administration in the present study resembled age-related impairments in rats and mice previously observed in this task. The cholinergic hypothesis of geriatric memory dysfunction appears to be implicated by these findings; however, the degree to which memory systems are involved remains unclear. Other performance variables such as discriminative control of stimuli or mechanisms of attention are implicated and discussed.

Animals↗

PubMed2003

In vivo pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol hydrochloride (SIB-1553A), a novel cholinergic ligand: microdialysis studies.

SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H3) and serotonergic (5-HT1 and 5HT2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 microM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1-40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (approximately 180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.

Acetylcholine↗

PubMed1984

Neurophysiological investigations in GM1 and GM2 gangliosidoses.

Neurophysiological studies (EEG, ERG, VEP and BAEP) have been carried out on a total of fifty-four patients (fourty-five GM2 and nine GM1 gangliosidosis) at various stages of the disease process. In infantile GM2 gangliosidosis, the EEG was midly abnormal from an early age but by the age of one year there was a rapid and progressive deterioration. EEG changes in late onset GM2 gangliosidosis were very variable and unrelated to age or enzyme defect. In both Type 1 and Type 2 GM1 gangliosidosis there was a progressive deterioration of the EEG. Paroxysmal features were not prominent in any of the gangliosidoses, despite the occurrence of seizures. The ERG remained normal in both GM2 and GM1 patients. In the infantile GM2 patients there was progressive loss of the VEP between nine and fifteen months of age but the timing of VEP changes were more variable in all the other groups. Evidence of brainstem dysfunction was found in one of the two TSD patients tested. The combined neurophysiological features appear to be characteristic for each group of gangliosidosis and differ from other neurometabolic disorders of childhood.

Arousal↗

PubMed2002

Serotonin transporter distribution and density in the cerebral cortex of alcoholic and nonalcoholic comparison subjects: a whole-hemisphere autoradiography study.

OBJECTIVE: Lesions of the medial prefrontal cortex and dysfunctions in serotonin turnover are two well-established factors associated with impulsive and sociopathic behaviors, but no firm neuroanatomical data have linked these pathophysiological findings. The aims of this study were to identify putative areas in the human brain that are rich in serotonin transporter sites, particularly within the medial prefrontal cortex, and to determine whether serotonin transporter density in this area is altered among alcoholic subjects. METHOD: Serotonin transporter density was measured among 17 alcoholic and 10 nonalcoholic comparison subjects by postmortem whole-hemisphere autoradiography with [(3)H]citalopram. RESULTS: In the human cerebral cortex, serotonin transporter binding sites were concentrated in the perigenual anterior cingulate cortex. Substantially sparser serotonin transporter density (up to 35%) was observed in the perigenual anterior cingulate cortex of alcoholic subjects in relation to nonalcoholic comparison subjects. After adjustment for age and postmortem delay, this finding remained statistically significant. CONCLUSIONS: A lower serotonin transporter density among the alcoholic subjects was observed, specifically in the so-called "affect" region, suggesting an association between ethanol addiction and dysfunctional serotonergic neurotransmission in this area.

Adolescent↗

PubMed1998

Oral zinc therapy in diabetic neuropathy.

The present double blind randomized study was conducted on 50 subjects; 20 age and sex matched healthy controls (Group--I); 15 patients of diabetes mellitus with neuropathy who received placebo for 6 weeks (Group--IIA); and 15 patients of diabetes mellitus with neuropathy who were given supplemental zinc sulphate (660 mg) for 6 weeks (Group--IIB). Serum zinc level, fasting blood sugar (FBS) and post prandial blood sugar (PPBS) levels and motor nerve conduction velocity (MNCV) were estimated on day 0 and after 6 weeks in all subjects. Serum zinc levels were significantly low (p < 0.001) in group IIA and IIB as compared to healthy controls (Group--I) at baseline. After 6 weeks the change in pre and post therapy values of FBS, PPBS and MNCV (median and common peroneal nerve) were highly significant (P = < 0.001) for group IIB alone with insignificant change (P = > 0.05) in group IIA. No improvement (P = > 0.05) in autonomic dysfunction was observed in either groups. Therefore, oral zinc supplementation helps in achieving better glycemic control and improvement in severity of peripheral neuropathy as assessed by MNCV.

Administration, Oral↗

PubMed2005

Targeting synapses and myelin in the prevention of schizophrenia.

Many of the functions that are mediated by the prefrontal cortex (PFC) are severely impaired in schizophrenia. The maturation of these functions takes place during late adolescence and early adulthood, which coincides with the period of time when overt symptomatology of schizophrenia most commonly emerges. Two developmental processes occurring during the periadolescence period appear to mediate the functional maturation of the PFC: pruning of exuberant synapses and myelination of axons. It has long been speculated in the literature that disturbances of these processes may result in dysfunction of the PFC and thereby trigger the emergence of symptoms and deficits of schizophrenia. Alternatively, but not mutually exclusively, it has also been suggested that these late developmental processes may not be aberrant but they "unmask" preexisting deficits in the PFC, resulting in the onset of symptoms. The important implication of both of these scenarios is that in either case the emergence of PFC functional disturbances and the onset of symptoms and deficits of schizophrenia would in theory be preventable by pharmacologic manipulation of the synaptic pruning and/or axonal myelination processes. Thus, better understanding of the cellular and molecular mechanisms that mediate these processes will provide truly novel insight into the therapeutics and prevention of schizophrenia.

Humans↗

PubMed1995

Crossed cerebellar diaschisis related to recurrent focal seizures.

After several days of recurrent focal motor seizures in a 32-year-old pregnant woman, a brain magnetic resonance imaging (MRI) scan showed signal abnormalities restricted to cerebral cortex and contralateral cerebellum that did not enhance after gadolinium administration. Maximal EEG dysfunction and seizure onset correlated anatomically with the area of image change. An aggressive medication regimen and termination of the pregnancy resulted in seizure control, reversal of postictal neurologic deficit, and improvement or resolution of the MRI and EEG abnormalities in 6 weeks. We concluded that the sequence of events suggested the reversible MRI lesions to be the result of repetitive seizure activity and that both localization and resolution of the lesions may be explained by reversible excitotoxic cell damage due to seizure-related excessive synaptic discharge.

Adult↗

PubMed2006

Human immunodeficiency virus type 1 gp120 inhibits long-term potentiation via chemokine receptor CXCR4 in rat hippocampal slices.

Human immunodeficiency virus type 1 (HIV-1) infection in its human host often results in progressive dementia and encephalopathy in adults and children, respectively. The mechanisms underlying virus-induced neurocognitive dysfunction are not fully understood. However, several studies strongly suggest that secretory viral and immune products from infected brain macrophages and microglia affect the onset and tempo of disease. One critical neurotoxin among these secretory products is the HIV-1 envelope glycoprotein gp120. To better understand how HIV-1 gp120 may affect cognitive function, we studied its effects on long-term potentiation (LTP) in the CA1 region of rat hippocampus, the brain region best linked to learning and memory. Although no effects were observed on basal synaptic transmission, HIV-1 gp120 inhibited LTP in a concentration-dependent manner in the presence of gamma-aminobutyric acid type A (GABAA) receptor antagonist. Heat-inactivated gp120 failed to block LTP. The HIV-1 gp120-mediated LTP inhibition was blocked by T140, a chemokine receptor CXCR4 antagonist, demonstrating gp120 inhibition of LTP via CXCR4. HIV-1 gp120 V3 loop peptides mimicked the inhibitory effects of HIV-1 gp120 protein on LTP. Monoclonal antibodies against the V3 loop epitope KRIHI eliminated the HIV-1 gp120 effects on LTP. These results further underscore the importance of HIV-1 gp120 in the pathogenesis of HIV-1-associated cognitive impairments seen during progressive viral infection.

Animals↗

PubMed2005

Effect of hypoxanthine on Na+,K+-ATPase activity and some parameters of oxidative stress in rat striatum.

The main objective of this study was to investigate the effects of preincubation of rat striatum homogenate in the presence of hypoxanthine, a metabolite accumulated in Lesch-Nyhan disease, on Na+,K+-ATPase activity and on some parameters of oxidative stress namely thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant parameter (TRAP) and membrane protein thiol content. Results showed that hypoxanthine significantly increased TBA-RS and reduced Na+,K+-ATPase activity, TRAP and membrane protein thiol content. In addition, we also evaluated the effect of glutathione, trolox, allopurinol and Nvarpi-nitro-L-arginine methyl ester (L-NAME) on the inhibitory effect of hypoxanthine on Na+,K+-ATPase activity in the same rat cerebral structure. All tested compounds per se did not alter Na+,K+-ATPase activity, but only glutathione and trolox prevented the effect of hypoxanthine on the enzyme activity. The effect of glutathione and trolox on hypoxanthine-induced increase of TBA-RS levels was also investigated. These antioxidants alone or combined with hypoxanthine reduced TBA-RS levels. Our present findings show that hypoxanthine induces oxidative stress in rat striatum and that the inhibition of Na+,K+-ATPase activity caused by this oxypurine was probably mediated by reactive oxygen species. It is presumed that these results might be associated with the neuronal dysfunction of patients affected by Lesch-Nyhan disease.

Animals↗

PubMed1997

Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia.

Multiple lines of evidence suggest that the prefrontal cortex is a site of dysfunction in schizophrenia. In addition, one of the characteristics of this disorder is the tendency for clinical symptoms to appear first during late adolescence or early adulthood. Recent studies in nonhuman primates have shown that the connectivity of the prefrontal cortex is substantially refined during adolescence, suggesting that these developmental changes may be critical for the appearance of the clinical features of schizophrenia. This article reviews data demonstrating that these late developmental changes are selective for particular neural elements in the prefrontal cortex and that they are synaptically linked. It is suggested that these neural elements comprise a functional circuit that is likely to be especially vulnerable in schizophrenia, a hypothesis that can be directly tested in postmortem studies.

Adolescent↗

PubMed2002

Aspects of neurodegeneration in the canine brain.

The process of neurodegeneration displays some common morphological characteristics, most of which are jointly observed in the brains of most mammalian species. In the canine brain, neurodegeneration is frequently typified by an extensive beta-amyloid (A beta) deposition (mainly of the C-terminal A beta1-42 form) within the neurones and at the synaptic regions, in the early stages of the process. These deposits subsequently appear to give rise to the formation of senile plaques of the diffuse (non-beta-sheet) subtype, which tend to develop spontaneously but rarely proceed to form neuritic plaques. Additional features accompanying neurodegeneration include accumulations of the "aging pigment," lipofuscin, intraneuronal changes in the cytoskeleton, vascular changes in the cerebrum, cortical cerebral atrophy, enlargement of the ventricles and increased concentration of oxidative stress markers, many of which are perceived as cardinal features of extensive dysfunction in the protein turnover network. The involvement of ubiquitin is discrete but consistent in many of these molecular structures and seems to account for some critical aspects of the associated neuropathology. Irrespective of these, though, the degenerated canine brain seems to be devoid of neurofibrillary tangle formation, a manifestation commonly observed in the brain of both aged (cognitively normal) and Alzheimer-affected human subjects. The fact that canines exhibit clear symptoms of an age-related cognitive decline pertains to the concept of A beta playing a central role in age-related cognitive dysfunction and neurodegeneration.

Animals↗

PubMed1992

Glutamatergic therapy of Huntington's chorea.

Preclinical evidence suggests that hypofunction of the glutamatergic subthalamopallidal tract may contribute to the hyperkinesis in Huntington's chorea. The clinical effects of milacemide, a glycine prodrug, were studied in seven patients with Huntington's disease under double-blind, placebo-controlled conditions. Oral doses of 1,200 mg/day did not alter chorea or cognitive dysfunction. Specific modulatory effects of glycine on the NMDA subtype of glutamate receptors, rather than the AMPA receptors, which may predominate among target neurons of the subthalamus, may explain the therapeutic failure of milacemide.

Acetamides↗

PubMed2005

HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway.

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC(50) = 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-D-aspartate (NMDA) receptor [D-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 microM), tetanus toxin (1 microM), P/Q/N type-calcium channel blockers (1 microM omega-agatoxin IVA and 1 microM omega-conotoxin GIVA) and bafilomycin A(1) (1 microM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.

Action Potentials↗

PubMed1994

[Functional studies of the spinal cord in chronic stenosing diseases of the cervical spine using somatosensory evoked potentials].

Report about 35 persons with chronic stenosing diseases of cervical spine which was investigated through somatosensory evoked potentials (SSEP) after stimulation of the median (M-SSEP), ulnar (U-SSEP) and tibial (T-SSEP) nerve. The examinations were always performed in extreme possible cervical ante and retroflexion. The majority of patients (n = 17) presented with a bony spinal stenosis. Less often were cervical disc prolaps (n = 8) or a atlanto-axial dislocation in primary chronic polyarthritis (n = 7) the cause of the illness. The rest of the patients (n = 3) had still different sources of stenoses of the spine. In 23 of 35 patients a change of the SSEP occurred during measurement while in this extreme cervical ante-and retroflexion. In 15 of these cases the initially pathological SSEP deteriorated, while in 8 patients an initially normal SSEP turned pathological in the functional position. Most often changes of the so-called "Functional SSEP" occurred in multisegmental bony cervical stenosis. In most cases a change in the T-SSEP obtained, independently of the main localisation of the radiologically verified spinal stenosis. The SSEP changes are illustrated through typical examples. The determination of SSEP in extreme positions of the cervical spine appears, therefore, as a suitable method to discover transient dysfunctions or the increase of dysfunctions of the cervical spinal cord. They can also serve as a preoperative screening method of dysfunctions of the cervical spinal cord in operations of planned long duration with unfavourable positioning of the cervical spine (extreme antiflexion, twisting, or retroflexion).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injury.

Traumatic brain injury (TBI) is a significant health issue that often causes enduring cognitive deficits, in particular memory dysfunction. The hippocampus, a structure crucial in learning and memory, is frequently damaged during TBI. Since long-term potentiation (LTP) is the leading cellular model underlying learning and memory, this study was undertaken to examine how injury affects area CA1 LTP in mice using lateral fluid percussion injury (FPI). Brain slices derived from FPI animals demonstrated an inability to induce LTP in area CA1 7 days postinjury. However, area CA1 long-term depression could be induced in neurons 7 days postinjury, demonstrating that some forms of synaptic plasticity can still be elicited. Using a multi-disciplined approach, potential mechanisms underlying the inability to induce and maintain area CA1 LTP were investigated. This study demonstrates that injury leads to significantly smaller N-methyl-D-aspartate potentials and glutamate-induced excitatory currents, increased dendritic spine size, and decreased expression of alpha-calcium calmodulin kinase II. These findings may underlie the injury-induced lack of LTP and thus, contribute to cognitive impairments often associated with TBI. Furthermore, these results provide attractive sites for potential therapeutic intervention directed toward alleviating the devastating consequences of human TBI.

Animals↗

PubMed2001

Chronic elevation of amyloid precursor protein in the neocortex or hippocampus of marmosets with selective cholinergic lesions.

In vitro studies have consistently demonstrated a link between cholinergic neurotransmission and amyloid precursor protein metabolism, although few studies have examined such a relationship in vivo and none have been conducted in primate species. The purpose of this study was to test the hypothesis that a reduction in cholinergic activity in neocortical and hippocampal areas consequent upon destruction of ascending cholinergic projections may lead to long-term changes in levels of amyloid precursor protein in these target areas in a primate species. The status of three synaptic proteins associated with neurotransmitter release, synaptophysin, syntaxin and SNAP-25, was also been examined. Selective immunolesions of the basal forebrain cholinergic projections led to increases in amyloid precursor protein-like immunoreactivity in hippocampus and cortex, measured 8 months postlesion. Furthermore, reductions in cortical and hippocampal SNAP-25, but not syntaxin or synaptophysin, immunoreactivity were observed. These results imply that the reduced cholinergic activity characteristic of Alzheimer's disease may contribute to the continuing emergence of neuropathology in addition to the well-known association with cognitive dysfunction.

Amyloid beta-Protein Precursor↗

PubMed2026

Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.

Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.

Animals↗