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 1,117 records · Page 62Linked to original sources

PubMed2001

Associations of defecography and physiologic findings in male patients with rectocele.

This study evaluated the incidence and physiological findings in male patients with rectoceles. All defecographic studies were evaluated by a single colorectal surgeon. After diagnosis of rectocele in male patients, the patient's history, symptoms, and physiologic tests (anal manometry, pudendal nerve terminal motor latency [PNTML], assessment and electromyography [EMG]) were studied. A prominent rectocele was defined as one that did not empty during defecography and was associated with outlet obstructive syndrome. Forty (17%) rectoceles were diagnosed in 234 male patients with evacuatory disorders who underwent defecography. Rectoceles were anterior in 19 (48%) and posterior in 21 (52%) patients. The main complaint was constipation with difficult defecation in 33 (83%), followed by rectal pain in 5 (13%), rectal prolapse in 1 (3%), and incontinence in 1 (3%). Previous prostatic surgery had been performed in 16 (40%) patients. The mean age and duration of symptoms were 72.4 years (range, 30-88) and 10.3 years (range, 0.5-70), respectively. Excessive straining during evacuation was noted in 73%, unilateral or bilateral pudendal neuropathy in 24.5%, paradoxical puborectalis contraction in 49% and abnormal EMG in 11% of patients. Higher resting pressures with a mean 3.9 cm high pressure zone were noted in 29% of patients. The accompanying findings in defecography were, non-relaxing or partially relaxing puborectalis muscle (66%), perineal descent (65%), intussusception (23%), and sigmoidocele (15%). None of the patients underwent surgery for rectocele alone. In conclusion, rectocele is uncommon in males; it rarely appears as an isolated dysfunction as it is often associated with functional disorders of the pelvic floor. There is a frequent association between rectocele and prostatectomy. Clinical significance and therapeutic strategy remain unknown.

Adult↗

PubMed2002

Neuropathology of sudden infant death (syndrome): literature review and evidence of a probable apoptotic degenerative cause.

BACKGROUND: The agonizing enigma of sudden infant death syndrome (SIDS) endures. Contemporary research concentrates on the central nervous system (CNS) as the prime cause. REVIEW AND DISCUSSION: What follows is a review of the neuropathology of SIDS. A persuasive, but as yet unproved, hypothesis is that the lethal pathophysiologic derangement or mechanism in SIDS involves dysfunction of sleep-related cardiorespiratory homeostatic controls or failure to arouse or both. Neuropathological investigation of SIDS continues to be closely linked to the study of specific anatomic structures and regions of the CNS. The structures in these regions underpin and regulate normal cardiorespiratory function. It follows that dysfunction of one or more of these loci probably precipitates SIDS. Under this large umbrella review we include histological, immunohistochemical, and biochemical markers in the cerebrospinal fluid (CSF), cerebrum, cerebellum, brain stem, pituitary gland, and pineal gland. With variable effect, these regions are deemed to mediate the functionality of cardiorespiratory activity and the diurnal rhythms of sleep/arousal. The following factors, which (a) are associated with altered electrochemical or neural transmission and biochemical changes in the CNS and (b) predispose to systemic derangements that most probably precipitate SIDS, are subjects of ongoing investigation: evidence of delayed development; ischemic insult; degenerative changes; and synaptic alterations. CONCLUSION: On the basis of current data, we add to these theoretical constructs by postulating that apoptotic neurodegeneration constitutes the anatomic substrate accounting for the pathophysiologic mechanism and proximate cause of SIDS.

Apoptosis↗

PubMed2001

Inhibition of rat brain Na+, K+-ATPase activity induced by homocysteine is probably mediated by oxidative stress.

The objective of the present study was to investigate the effects of preincubation of hippocampus homogenates in the presence of homocysteine or methionine on Na+, K+-ATPase and Mg2+-ATPase activities in synaptic membranes of rats. Homocysteine significantly inhibited Na+, K+-ATPase activity, whereas methionine had no effect. Mg2+-ATPase activity was not altered by the metabolites. We also evaluated the effect of incubating glutathione, cysteine, dithiothreitol, trolox, superoxide dismutase and GM1 ganglioside alone or incubation with homocysteine on Na+, K+-ATPase activity. Tested compounds did not alter Na+, K+-ATPase and Mg2+-ATPase activities, but except for trolox, prevented the inhibitory effect of homocysteine on Na+, K+-ATPase activity. These results suggest that inhibition of this enzyme activity by homocysteine is possibly mediated by free radicals and may contribute to the neurological dysfunction found in homocystinuric patients.

Animals↗

PubMed2003

Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission.

OBJECTIVE: Functional autoantibodies that inhibit M(3) muscarinic receptor (M3R)-mediated neurotransmission have been reported in patients with Sjögren's syndrome (SS) and in patients with scleroderma. Because of limited reports that intravenous immunoglobulin (IVIG) improves dysautonomia in primary SS, we investigated whether IVIG neutralizes the effect of anti-M3R antibodies on colon smooth muscle contractions, in an in vitro functional assay. METHODS: IgG obtained from patients with primary SS, patients with rheumatoid arthritis and secondary SS, and patients with scleroderma was tested, before and after coincubation with equimolar amounts of IVIG or its F(ab')(2) and Fc fractions, for the ability to inhibit carbachol-evoked colon smooth muscle contractions. In addition, patient IgG was passed through an IVIG F(ab')(2) column, and unretained IgG was tested for functional activity on colon smooth muscle strips. Purified IgG obtained from healthy adults was also examined for a neutralizing effect on anti-M3R antibody activity. RESULTS: Inhibition of colon contractions was mediated by the Fab fraction of patient IgG. Coincubation of IgG from the 3 patient groups with IVIG or its F(ab')(2) fragment neutralized anti-M3R antibody-mediated inhibition of cholinergic smooth muscle contractions. Preabsorption of patient IgG with Sepharose-bound IVIG F(ab')(2) removed the anti-M3R inhibitory activity. In addition, purified IgG from each of 4 healthy adults neutralized the functional autoantibodies. CONCLUSION: Anti-M3R antibody activity does not require receptor crosslinking. Antiidiotypic antibodies present in pooled IgG neutralize patient IgG-mediated inhibition of M3R cholinergic neurotransmission, providing a rationale for IVIG as a treatment of autonomic dysfunction in patients with SS and patients with scleroderma. Furthermore, antiidiotypic antibodies in healthy individuals may prevent the emergence of pathogenic anti-M3R autoantibodies.

Acetylcholine↗

PubMed2004

Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy.

A dysfunction of amino acid neurotransmitter transporters occurs in a number of central nervous system disorders, including stroke, epilepsy, cerebral palsy and amyotrophic lateral sclerosis. This dysfunction can comprise a reversal of transport direction, leading to the release of neurotransmitter into the extracellular space, or an alteration in transporter expression level. This review analyses the role of glutamate and GABA transporters in the pathogenesis and therapy of a number of acute and chronic neurological disorders.

Acute Disease↗

PubMed2006

Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction.

Dopaminergic dysregulation can cause motor dysfunction, but the mechanisms underlying dopamine-related motor disorders remain under debate. We used an inducible and reversible pharmacogenetic approach in dopamine transporter knockout mice to investigate the simultaneous activity of neuronal ensembles in the dorsolateral striatum and primary motor cortex during hyperdopaminergia ( approximately 500% of controls) with hyperkinesia, and after rapid and profound dopamine depletion (<0.2%) with akinesia in the same animal. Surprisingly, although most cortical and striatal neurons ( approximately 70%) changed firing rate during the transition between dopamine-related hyperkinesia and akinesia, the overall cortical firing rate remained unchanged. Conversely, neuronal oscillations and ensemble activity coordination within and between cortex and striatum did change rapidly between these periods. During hyperkinesia, corticostriatal activity became largely asynchronous, while during dopamine-depletion the synchronicity increased. Thus, dopamine-related disorders like Parkinson's disease may not stem from changes in the overall levels of cortical activity, but from dysfunctional activity coordination in corticostriatal circuits.

Action Potentials↗

PubMed2026

A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.

Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and by recycling building blocks for organelle biogenesis. Lysosomal storage disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons. In-depth abundance and correlation profiling across organelles and suborganelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein-protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryoelectron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.

Humans↗

PubMed1999

High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by a wide array of methodologies, the neurobiochemical substrate of this disorder is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with ADHD through use of positron emission tomography and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic terminals, a measure of dopa decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children with ADHD than in 10 normal children. Despite its magnitude, this difference would not have reached statistical significance if corrected by the Bonferroni test for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated with symptom severity. No other dopamine-rich regions significantly differed between groups. CONCLUSIONS: These findings are suggestive of dopaminergic dysfunction at the level of the dopaminergic nuclei in children with ADHD. Abnormality in dopa decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter, degradation enzymes). Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD.

Adolescent↗

PubMed1999

Neural features of recovery from CNS injury revealed by PET in human brain.

Dysfunction of the brain occurring after local brain injury often improves clinically; however, the reason for this improvement has not been scientifically clarified. We used a new technique for imaging phosphoinositide turnover, carbon-11-labeled diacylglycerol-positron emission tomography, to observe the process of recovery from injury in human brain. Patients with local brain injury exhibited radioactive spots located in the association areas distant from the lesion, while normal controls did not exhibit such spots. These findings indicated one of possible features of the neural recovery from the central nervous system injury, which appears to play a role in modulation of synaptic transmission in the intact brain. Conventionally, attention has been directed primarily to areas surrounding brain injury, such as the penumbra; however, the present study suggests that initiation of reorganization of neural connections occurs in remote cortex.

Adult↗

PubMed2005

Alternative pathways for catecholamine action in oral motor control.

Orofacial movement is a complex function performed by facial and jaw muscles. Jaw movement is enacted through the triggering of motoneurons located primarily in the trigeminal motor nucleus (Mo5). The Mo5 is located in the pontine reticular formation, which is encircled by premotor neurons. Previous studies using retrograde tracers have demonstrated that premotor neurons innervating the Mo5 are distributed in brainstem areas, and electrophysiological studies have suggested the existence of a subcortical relay in the corticofugal-Mo5 pathway. Various neurotransmitters have been implicated in oral movement. Dopamine is of special interest since its imbalance may produce changes in basal ganglia activity, which generates abnormal movements, including jaw motor dysfunction, as in oral dyskinesia and possibly in bruxism. However, the anatomical pathways connecting the dopaminergic systems with Mo5 motoneurons have not been studied systematically. After injecting retrograde tracer fluorogold into the Mo5, we observed retrograde-labeled neurons in brainstem areas and in a few forebrain nuclei, such as the central nucleus of the amygdala, and the parasubthalamic nucleus. By using dual-labeled immunohistochemistry, we found tyrosine hydroxylase (a catecholamine-processing enzyme) immunoreactive fibers in close apposition to retrograde-labeled neurons in brainstem nuclei, in the central nucleus of the amygdala and the parasubthalamic nucleus, suggesting the occurrence of synaptic contacts. Therefore, we suggested that catecholamines may regulate oralfacial movements through the premotor brainstem nuclei, which are related to masticatory control, and forebrain areas related to autonomic and stress responses.

Amygdala↗

PubMed2004

Abnormalities of dopaminergic neurotransmission in SCA2: a combined 123I-betaCIT and 123I-IBZM SPECT study.

Extrapyramidal features may occur in spinocerebellar ataxias consistent with neuropathological evidence of nigrostriatal involvement. Recently, striatal dopaminergic neurotransmission was found to be abnormal in the uncommon parkinsonian presentation of spinocerebellar ataxia type 2 (SCA2). We have investigated, therefore, striatal dopamine transporter and D2 receptor function in a series of 9 patients with the more common ataxic presentation of SCA2 using single photon emission computed tomography and beta-CIT as well as IBZM. Age-matched healthy subjects and patients with Parkinson's disease (PD) served as controls. All except 1 SCA2 patient exhibited slowness of limb movements without rigidity or rest tremor. In addition, cervical dystonia was present in 5 and dystonic head tremor in 2 SCA2 patients. Striatocerebellar (S/C) ratios of beta-CIT binding were significantly reduced in SCA2 patients compared to control subjects, and they were within the range of PD patients. S/C ratios of IBZM binding were significantly reduced in SCA2 patients compared to control subjects. We conclude that dopaminergic neurotransmission is impaired in the ataxic presentation of SCA2, with a prominent loss of striatal dopamine transporter function. Both slowness of limb movements as well as dystonia in the ataxic SCA2 phenotype may reflect dysfunction not only at cerebellar but also at basal ganglia level.

Adult↗

PubMed2006

Intensity dependence of auditory-evoked cortical potentials in fibromyalgia patients: a test of the generalized hypervigilance hypothesis.

UNLABELLED: On the basis of recent evidence concerning the amplification of incoming stimulation in fibromyalgia (FM) patients, it has been proposed that a generalized hypervigilance of painful and nonpainful sensations may be at the root of this disorder. So far, research into this issue has been inconclusive, possibly owing to the lack of agreement as to the operational definition of "generalized hypervigilance" and to the lack of robust objective measures characterizing the sensory style of FM patients. In this study, we recorded auditory-evoked potentials (AEPs) elicited by tones of increasing intensity (60, 70, 80, 90, and 105 dB) in 27 female FM patients and 25 healthy controls. Fibromyalgia patients presented shorter N1 and P2 latencies and a stronger intensity dependence of their AEPs. Both results suggest that FM patients may be hypervigilant to sensory stimuli, especially when very loud tones are used. The most noteworthy difference between patients and control subjects is at the highest stimulus intensity, for which far more patients maintained increased N1-P2 amplitudes in relation to the 90-dB tones. The larger AEP amplitudes to the 105-dB tones suggest that defects in an inhibitory system protecting against overstimulation may be a crucial factor in the pathophysiology of FM. Because a stronger loudness dependence of AEPs has been related to weak serotonergic transmission, it is hypothesized that for many FM patients deficient inhibition of the response to noxious and intense auditory stimuli may be due to a serotonergic deficit. PERSPECTIVE: The study of auditory-evoked potentials in response to tones of increasing intensity in FM patients may help to clarify the pathophysiology of this disorder, especially regarding the role of inhibition deficits involving serotonergic dysfunction, and may be a useful tool to guide the pharmacologic treatment of FM patients.

Acoustic Stimulation↗

PubMed2004

PET evidence for a role of the basal ganglia in patients with ring chromosome 20 epilepsy.

BACKGROUND: Studies in animal models and epileptic patients have suggested that circuits of the basal ganglia may control epileptic seizures and that striatal dopaminergic transmission plays a key role in seizure interruption. Ring chromosome 20 (r[20]) epilepsy is a very homogenous type of epilepsy and is clinically characterized by long-lasting seizures suggesting a dysfunction in the seizure control system. The hypothesis that these long-lasting seizures are associated with a reduction of striatal dopamine was addressed in the present study in drug-resistant patients with r(20) epilepsy using PET. METHOD: The authors performed [18F]fluoro-l-DOPA PET in 14 patients with r(20) epilepsy and compared uptake constants in the putamen and the caudate with those of 10 controls. In addition, the authors examined the correlation between these constants and the percentage of cells with r(20) mosaicism. RESULTS: [18F]fluoro-l-DOPA uptake was significantly decreased bilaterally in the putamen and in the caudate nucleus of patients. This reduction was equal for both nuclei and was not correlated to the percentage of cells with r(20). CONCLUSION: Striatal dopamine is modulated in r(20) epilepsy; dysfunction of this neurotransmission may impair the mechanisms that interrupt seizures.

Adolescent↗

PubMed2001

Pharmacological MRI mapping of age-associated changes in basal ganglia circuitry of awake rhesus monkeys.

While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson's disease (PD) are well studied, little is known about functional changes in the neural circuitry of this area during normal aging. Here we report the first survey of age-associated changes in the basal ganglia of behaviorally characterized, awake rhesus monkeys, using pharmacological MRI to map responses to dopaminergic stimulation. Apomorphine, a mixed D(1)/D(2) dopamine receptor agonist, evoked little change in the substantia nigra (SN) of aged animals while significantly reducing activation in young adult monkeys. Compared to young animals, both apomorphine and d-amphetamine (which increases synaptic dopamine levels) significantly increased activation of the aged rhesus globus pallidus externa (GPe). In addition, the aged animals showed decreased activity in the putamen in response to d-amphetamine administration. Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD, the apomorphine-evoked activation of their GPe corresponded with apomorphine-induced increases in neuronal activity seen in Parkinson's patients and animal models. Given the major role of the GPe in regulating motor behavior, the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age.

Aging↗

PubMed1998

Mood and neuropsychological function in depression: the role of corticosteroids and serotonin.

BACKGROUND: Depressed patients show deficits on neuropsychological tests. However, the basis of these impairments and their relationship with mood disturbance remains unclear. METHODS: This paper reviews the literature regarding the relationship between mood disturbance and neuropsychological impairment in depression and the evidence for serotonergic and hypothalamic-pituitary-adrenal (HPA) axis involvement in these two domains. RESULTS: Mood disturbance and neuropsychological impairment both occur in depression, but have no clear relationship in time or degree. Impairment of post-synaptic 5-HT1A receptor function may result in the symptom of low mood in depression. Depressed patients demonstrate abnormalities in the functional control of the HPA axis with a resultant hypercortisolaemia, which may impair neuropsychological function. These processes may be related given the extensive interactions between the serotonergic system and the HPA axis. CONCLUSIONS: We argue that there is a neurobiological cause of impaired neuropsychological function in depression. The complex relationship between neuropsychological function and mood may be a result of interactions between the serotonergic system and the HPA axis, particularly in the hippocampus with involvement of serotonergic 5-HT1A and glucocorticoid receptors. A primary dysfunction in these receptors will produce a lowering of mood and neuropsychological impairment respectively. Either dysfunction will result in a secondary impairment of the alternate system. Thus, the effective and psychological changes of depressive illness are likely to have complex relationships in time and severity to one another and the illness as a whole may result from a range of primary aetio-pathologies.

Adrenal Cortex Hormones↗

PubMed1993

Autoimmune myasthenia gravis.

The evident defect in this disease is postsynaptic dysfunction due to anti-acetylcholine receptor antibodies. The postsynaptic membrane is simplified, the number of acetylcholine receptors is reduced, and neuromuscular transmission is impaired. Antiacetylcholinesterase drugs still play a role in management. Newer options include prednisone, azathioprine, and cyclosporine.

Adult↗

PubMedDate not supplied

Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats.

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the beta-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.

Animals↗

PubMed2002

Xerostomia and you.

The aims of management of patients with xerostomia include the provision of a definitive aetiology and diagnosis, and a prognosis for the salivary dysfunction. Salivary flow assessment and function testing, other relevant laboratory tests, and even referrals should be performed as necessary. Management of the condition depends on diagnosis and severity, and includes enhancement of salivary flow, oral lubrication, control of soft-tissue infections and discomfort, and prevention of dental caries.

Cariostatic Agents↗