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 1,279 records · Page 71Linked to original sources

PubMed2000

Nicotinic acetylcholine receptors in the autonomic control of bladder function.

Micturition is achieved through complex neurological mechanisms involving somatic, autonomic and central components. This article briefly reviews recent findings on the autonomic control of urinary bladder function. Neuronal nicotinic acetylcholine receptors mediate fast synaptic transmission in autonomic ganglia, and activation of nicotinic receptors in parasympathetic bladder neurons produces contraction of the detrusor muscle. Autonomic ganglia contain transcripts for the alpha(3), alpha(4), alpha(5), alpha(7), beta(2) and beta(4) nicotinic subunits, which can assemble to form multiple nicotinic receptor subtypes, but the exact nicotinic receptor subunit composition in bladder ganglia is unknown. Mutant mice lacking the alpha(3) or the beta(2) and the beta(4) nicotinic subunits have enlarged bladders with dribbling urination and develop urinary infection and bladder stones. Bladder strips from alpha(3) null mice do not respond to nicotine but contract when stimulated with a muscarinic agonist or electric field stimulation. Mice lacking the beta(2) subunit have no overt bladder phenotype, and their bladders contract in response to nicotine. Surprisingly, bladder strips from beta(4) mutant mice do not respond to nicotine despite the absence of major bladder dysfunction in vivo. These findings suggest that nicotinic receptors containing the alpha(3) and the beta(4) subunits are necessary for normal bladder function.

Animals↗

PubMed2001

The neurophysiological meaning of auditory P300 in subtypes of schizophrenia.

Event-related potentials are a powerful tool to investigate the real-time course of brain electrical mass activation during cognitive processing. In several psychiatric disorders, differences compared to healthy subjects have been reliably described. The specificity and the pathophysiological meaning of the findings were unclear in most studies, however. This review summarizes methodological aspects and findings, in healthy subjects and psychiatric patients, of investigations based on the auditory oddball paradigm, which evokes the P300 component of event-related potentials. Recent convergent results from P300 and brain imaging studies allowed the interpretation of P300 findings in psychotic disorders in terms of different specific and meaningful neurophysiological disturbances. Namely, core schizophrenia is characterized by a left-temporal dysfunction associated with deficits in verbal processing. Acute remitting schizophrenia-like psychoses (cycloid psychosis, ICD-10 F23), on the other hand, show normal hemispheric balance but consistent signs of cerebral hyperarousal. Recent studies further indicate that the drive for action of manic patients does not rely on over-excitation but rather on frontal disinhibition. The findings may help to further advance the understandings and sub-grouping of functional psychoses based on pathophysiological mechanisms.

Arousal↗

PubMed2005

Transynaptic effects of tetanus neurotoxin in the oculomotor system.

The question whether general tetanus arises from the independent sum of multiple local tetani or results from the actions of the transynaptic tetanus neurotoxin (TeNT) in higher brain centres remains unresolved. Despite the blood-borne dissemination of TeNT from an infected wound, the access to the central nervous system is probably prevented by the blood-brain barrier. However, several long-term sequelae (e.g. autonomic dysfunction, seizures, myoclonus, and sleep disturbances) present after the subsidence of muscle spasms might be indicative of central actions that occur farther away from lower motoneurons. Subsequently, the obvious entry route is the peripheral neurons followed by the transynaptic passage to the brain. We aimed at describing the pathophysiological correlates of TeNT translocation using the oculomotor system as a comprehensive model of cell connectivity and neuronal firing properties. In this study, we report that injection of TeNT into the medial rectus muscle of one eye resulted in bilateral gaze palsy attributed to firing alterations found in the contralaterally projecting abducens internuclear neurons. Functional alterations in the abducens-to-oculomotor internuclear pathway resembled in part the classically described TeNT disinhibition. We confirmed the transynaptic targeted action of TeNT by analysing vesicle-associated membrane protein2 (VAMP2) immunoreactivity (the SNARE protein cleaved by TeNT). VAMP2 immunoreactivity decreased by 94.4% in the oculomotor nucleus (the first synaptic relay) and by 62.1% presynaptic to abducens neurons (the second synaptic relay). These results are the first demonstration of physiological changes in chains of connected neurons that are best explained by the transynaptic action of TeNT on premotor neurons as shown with VAMP2 immunoreactivity which serves as an indicator of TeNT activity.

Abducens Nerve↗

PubMed2000

Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression.

Neuroimaging studies of major depression have identified neurophysiological abnormalities in multiple areas of the prefrontal cortex (PFC), the amygdala, and related parts of the striatum and thalamus. Some of these abnormalities are mood state-dependent, and appear in regions where cerebral blood flow (CBF) increases during other normal and pathological emotional states. These neurophysiological differences between depressives and non-depressed controls may thus locate areas where physiological activity changes to mediate or respond to the emotional, behavioral and cognitive manifestations of major depressive episodes (MDE). Other abnormalities persist following symptom remission, and are found in orbital and medial PFC areas where post mortem studies demonstrate reductions in cortex volume and/or histopathological changes in primary mood disorders. These orbital and medial PFC areas have been shown by other types of evidence to modulate emotional behavior and stress responses, suggesting that dysfunction involving these regions may be involved in the pathogenesis of depressive symptoms. Finally, physiological activity is decreased during MDE in dorsal PFC areas implicated in language, selective attention, visuospatial or mnemonic processing, but these abnormalities reverse with symptom remission. These areas of 'deactivation' during the depressed state may reflect neurophysiological interactions between cognitive and emotional processing, and may relate to the subtle cognitive impairments associated with MDE.

Adoption↗

PubMed2005

Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice.

Although of clinical importance, little is known about the mechanism of seizure in neuronal ceroid lipofuscinosis (NCL). In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D-deficient (CD-/-) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL. In hippocampal slices prepared from CD-/- mice at post-natal day (P)24, spontaneous burst discharges were recorded from CA3 pyramidal cells. At P24, the mean amplitude of IPSPs after stimulation of the mossy fibres was significantly smaller than that of wild-type mice, which was substantiated by the decreased level of gamma-aminobutyric acid (GABA) contents in the hippocampus measured by high-performance liquid chromatography (HPLC). At this stage, activated microglia were found to accumulate in the pyramidal cell layer of the hippocampal CA3 subfield of CD-/- mice. However, there was no significant change in the numerical density of GABAergic interneurons in the CA3 subfield of CD-/- mice at P24, estimated by counting the number of glutamate decarboxylase (GAD) 67-immunoreactive somata. In the hippocampus and the cortex of CD-/- mice at P24, some GABAergic interneurons displayed extremely high somatic granular immunoreactivites for GAD67, suggesting the lysosomal accumulation of GAD67. GAD67 levels in axon terminals abutting on to perisomatic regions of hippocampal CA3 pyramidal cells was not significantly changed in CD-/- mice even at P24, whereas the total protein levels of GAD67 in both the hippocampus and the cortex of CD-/- mice after P24 were significantly decreased as a result of degradation. Furthermore, the recombinant human GAD65/67 was rapidly digested by the lysosomal fraction prepared from the whole brain of wild-type and CD-/- mice. These observations strongly suggest that the reduction of GABA contents, presumably because of lysosomal degradation of GAD67 and lysosomal accumulation of its degraded forms, are responsible for the dysfunction of GABAergic interneurons in the hippocampal CA3 subfield of CD-/- mice.

Animals↗

PubMed2004

Human neural stem/progenitor cells, expanded in long-term neurosphere culture, promote functional recovery after focal ischemia in Mongolian gerbils.

Transplantation of human neural stem cells (NSCs) is a promising potential therapy for neurologic dysfunctions after the hyperacute stage of stroke in humans, but large amounts of human NSCs must be expanded in long-term culture for such therapy. To determine their possible therapeutic potential for human stroke, human fetal neural stem/progenitor cells (NSPCs) (i.e., neurosphere-forming cells) were isolated originally from forebrain tissues of one human fetus, and expanded in long-term neurosphere culture (exceeding 24 weeks), then xenografted into the lesioned areas in the brains of Mongolian gerbils 4 days after focal ischemia. Sensorimotor and cognitive functions were evaluated during the 4 weeks after transplantation. The total infarction volume in the NSPC-grafted animals was significantly lower than that in controls. Approximately 8% of the grafted NSPCs survived, mainly in areas of selective neuronal death, and were costained with antibodies against neuronal nuclei antibody (NeuN), microtubule associated protein (MAP-2), glial fibrillary acidic protein (GFAP), and anti-2'3' cyclic nucleotide 3'-phosphodiesterase (CNPase). Synaptic structures between NSPCs-derived neurons and host neurons were observed. Furthermore, gradual improvement of neurologic functions was observed clearly in the NSPC-grafted animals, compared to that in controls. Human NSPCs, even from long-term culture, remarkably improved neurologic functions after focal ischemia in the Mongolian gerbil, and maintained their abilities to migrate around the infarction, differentiate into mature neurons, and form synapses with host neuronal circuits. These results indicate that in vitro-expanded human neurosphere cells are a potential source for transplantable material for treatment of stroke.

Animals↗

PubMed1986

An examination of parkinsonian versus anhedonia contributions to self-stimulation impairments induced by dopamine dysfunction.

Interference with brain dopamine neurotransmission can severely impair brain stimulation reward behavior. The significance of this impairment in reward behavior, however, has been a problematic issue. That is, it has been difficult to determine whether the dopamine dysfunction has attenuated the reward effect of the stimulation or has merely rendered the animal less able to generate the behavior required to obtain reinforcement. To experimentally re-assess this issue, the present studies examine the effect of unilateral 6-hydroxydopamine lesions of forebrain dopamine neurons on brain stimulation reward in animals. In general, these studies highlight the substantial motoric deficits produced by the lesion treatments. By combining lesion and neuroleptic drug treatments, however, it appeared that effects on reward could be detected.

Animals↗

PubMedDate not supplied

Electroretinographic and clinicopathologic correlations of retinal dysfunction in infantile neuronal ceroid lipofuscinosis (infantile Batten disease).

Infantile neuronal ceroid lipofuscinosis (INCL) is an autosomal recessive disease that results from deficiency of palmitoyl-protein thioesterase-1 (PPT1). INCL leads to retinal blindness, neurodegeneration, and early death. We studied the clinical features and electroretinogram (ERG) in three patients and histopathologic and immunofluorescence analyses of the retina in the third patient, who died at 3 years 2 months of age. The ERGs for the 2 youngest patients (ages 1.7 and 2.3 years) showed normal scotopic bright flash a-wave amplitudes with severe loss of b-wave (electronegative ERG), indicating dysfunction at or proximal to the photoreceptor inner segments. The third patient at 2.9 years of age showed subnormal a-wave amplitudes and even greater loss of b-wave amplitudes. Histopathology revealed reduced cell numbers in all retinal layers, including the inner nuclear layer (INL), and a central epiretinal membrane. Autofluorescent lipofuscin granules were present in all neuronal cell types in the retina. Cones and rods in the parafoveal area were labeled with a cone cytoplasmic marker, mAb 7G6, and anti-rhodopsin, respectively, and had extremely short outer segments. The periphery showed better preservation but photoreceptor outer segments were short. Immunofluorescence revealed degenerate rods and cones throughout the retina with better preservation in the periphery. Autofluorescent lipofuscin was found in all cell types, including cone inner segments, to a greater degree than seen in normal ageing. The ERG findings support the existence early in the disease of a relative pre- or post-synaptic block of effective neurotransmission from photoreceptor inner segments to the second order bipolar neurons.

Child, Preschool↗

PubMed2006

Prolonged intracortical delay of long-latency reflexes: electrophysiological evidence for a cortical dysfunction in multiple sclerosis.

Convincing evidence suggests that long-latency reflexes (LLRs) are capable of testing the transcortical sensorimotor reflex arch. By subtracting the sum of the latencies of N20 (afferent branch) and transcranially elicited motor evoked potentials (MEP; efferent branch) from the LLR II latency, the cortical relay time (CRT) can also be obtained, which is alleged to represent the time required for the cortical sensorimotor integration. The aim of the present study was to investigate if a cortical dysfunction occurs in multiple sclerosis (MS). Median nerve somatosensory evoked potentials (SEPs), MEPs and LLRs were recorded from the upper limbs of 23, not severely disabled MS patients in acute phases of the disease. Eighteen age and sex matched healthy volunteers served as controls. N20, MEP, LLR II latencies were measured, and the CRT was calculated for each limb. The statistical comparison between patients and controls was only weakly significant by taking into account conduction times along either the afferent (N20) or the efferent (MEP) pathways. On the contrary, it turned out to be considerably significant if both branches of the transcortical sensorimotor reflex arch, together with the intracortical pathway, were simultaneously tested by means of the LLRs. Moreover, the patients showed a significantly higher CRT compared with that found in the control subjects. These findings are consistent with a prolonged intracortical delay of LLRs in the MS group and suggest the occurrence of conduction velocity slowing and/or synaptic transmission impairment along the sensorimotor intracortical pathway in MS.

Adult↗

PubMed2000

New neurochemical markers for psychosis: a working hypothesis of their operation.

Reelin (Reln) is expressed in specific GABAergic neurons in layer I and II of neocortex, and is secreted into the extracellular matrix where it surrounds dendrites, spines and neurite arborizations, and binds to integrin receptors located on post-synaptic densities of apical dendritic spines. Experiments in rodents (including wild type or reeler heterozygous mice) and non-human primates suggest the Reln secreted in the extracellular matrix of neocortex, via integrin receptors, modulates the function of the adaptor protein DAB1(drosophila disable-gene) homologous product) thereby participating in dynamic processes associated with plasticity changes in dendrites, dendritic spines and their synapses. A local protein synthesis at dendritic spines (ie the activity regulated cytoskeleton associated protein, Arc) probably acts as a signal for plastic modulatory activities in synapses operative in neural group interactions. A research strategy directed toward identifying specific neurochemical markers operative in the etiopathology of psychotic disorders lead to the identification of a downregulation (30-50%) of Reln and glutamic acid decarboxylase 67(GAD67) expression in prefrontal cortex and other brain areas of schizoprenia and bipolar disorder patients with psychosis. These downregulations were not due to neuronal damage, postmortem interval, or antipsychotic medication. The dysfunction of GABAergic interneurons observed in psychotic brains in combination with reduced Reln expression and downregulation of Reln-integrin receptor interaction, may provide an explanation for the reported decrease in neuropile expression including dendritic spine density reduction, in neocortex of schizophrenia patients. This downregulation of neuropile plasticity may be a factor to be considered in the etiology of the disintegration of consciousness, which is one of the primary signs of psychosis.

Animals↗

PubMed2005

Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat.

Ageing is characterized by deficits in learning and memory and by a deficit in long-term potentiation (LTP) in hippocampus. Several age-related changes, including dysfunction of calcium homeostatic mechanisms and upregulation of inflammatory processes are likely to contribute to these deficits. Here we exploited the fact that aged rats fall into a subgroup which fail to sustain LTP in perforant path granule cell synapses as a result of tetanic stimulation, and a subgroup which sustains LTP in a manner indistinguishable from young rats, in an effort to identify differential changes in the two subgroups. The age-related increase in IL-1beta concentration and IL-1beta-induced signalling was more profound in aged rats which failed to sustain LTP. We demonstrate that functional IL-4 receptors are expressed in rat hippocampus and that age is associated with a decrease in IL-4 concentration accompanied by a decrease in phosphorylation of JAK-1 and STAT-6. We propose that the imbalance between pro-inflammatory and anti-inflammatory cytokines in the aged brain significantly contributes to age-related deficits in synaptic function.

Age Factors↗

PubMed2001

Sympathetic nerve biology in essential hypertension.

1. Although the importance of sympathetic nervous activation in the pathogenesis of essential hypertension is well documented, the exact pathophysiology of the sympathetic nervous dysfunction present remains to be delineated. There are several possible explanations for the increased spillover of noradrenaline from the kidneys and heart to plasma, a key piece of evidence supporting the neurogenic basis of essential hypertension, in addition to the obvious one of an increased rate of sympathetic nerve firing. 2. The possibility that there may be an increase in the density of sympathetic innervation in human hypertension, well documented in the spontaneously hypertensive rat, is currently under investigation by us. 3. Adrenaline cotransmission is present in the cardiac sympathetic nerves of patients with essential hypertension, presumptive evidence of their exposure to high levels of stress and a possible basis for the observed increase in cardiac noradrenaline spillover, through presynaptic augmentation of noradrenaline release. 4. Phenotypic evidence exists also of faulty noradrenaline reuptake into the sympathetic nerves of the heart in essential hypertension, an abnormality that would amplify the sympathetic neural signal by impairing removal of noradrenaline from the synaptic cleft.

Aging↗

PubMed2006

Mechanisms of oral somatosensory and motor functions and their clinical correlates.

This article provides a review of somatosensory and motor pathways and processes involved in oral sensorimotor function and dysfunction. It reviews somatosensory processes in peripheral tissues, brainstem and higher brain centres such as thalamus and cerebral cortex, with a particular emphasis on nociceptive mechanisms. It also outlines some of the circuits and processes involved in reflexes and motor control. In addition, it emphasizes the concept of neuroplasticity and its applicability to oro-facial pain, to motor control and motor learning, and to adaptation to changes in the oral sensory environment such as may occur with the placement of dental implants.

Animals↗

PubMed2003

Essential fatty acids and the brain.

OBJECTIVE: To review the role of essential fatty acids in brain membrane function and in the genesis of psychiatric disease. METHOD: Medline databases were searched for published articles with links among the following key words: essential fatty acids, omega-3 fatty acids, docosahexanoic acid, eicosapentanoic acid, arachidonic acid, neurotransmission, phospholipase A2, depression, schizophrenia, mental performance, attention-deficit hyperactivity disorder, and Alzheimer's disease. Biochemistry textbooks were consulted on the role of fatty acids in membrane function, neurotransmission, and eicosanoid formation. The 3-dimensional structures of fatty acids were obtained from the Web site of the Biochemistry Department, University of Arizona (2001). RESULTS: The fatty acid composition of neuronal cell membrane phospholipids reflects their intake in the diet. The degree of a fatty acid's desaturation determines its 3-dimensional structure and, thus, membrane fluidity and function. The ratio between omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), in particular, influences various aspects of serotoninergic and catecholaminergic neurotransmission, as shown by studies in animal models. Phospholipase A2 (PLA2) hydrolyzes fatty acids from membrane phospholipids: liberated omega-6 PUFAs are metabolized to prostaglandins with a higher inflammatory potential, compared with those generated from the omega-3 family. Thus the activity of PLA2 coupled with membrane fatty acid composition may play a central role in the development of neuronal dysfunction. Intervention trials in human subjects show that omega-3 fatty acids have possible positive effects in the treatment of various psychiatric disorders, but more data are needed to make conclusive directives in this regard. CONCLUSION: The ratio of membrane omega-3 to omega-6 PUFAs can be modulated by dietary intake. This ratio influences neurotransmission and prostaglandin formation, processes that are vital in the maintenance of normal brain function.

Aged↗

PubMed2000

Serotonergic decompensation in the akinetic expression of Parkinson's disease.

The current diagnostic and treatment paradigm for the akinetic form of Parkinson's disease asserts that the majority of symptoms and treatment phenomena arise from a dysfunctional dopaminergic system. Recent studies have attempted to determine the roles of other biogenic amine neurotransmitters such as serotonin and norepinephrine. Metabolic breakdown product studies of Parkinsonian and non-Parkinsonian cerebrospinal fluid (CSF) samples indicate significant differences in the levels of serotonin and norepinephrine in addition to the levels of dopamine. Such changes may suggest that current pharmacologic therapies that attempt to restore only dopamine are inadequate, and require accompanying therapies to elevate serotonin and norepinephrine levels.

Brain↗

PubMed2004

Pathophysiology of tethered cord syndrome: correlation with symptomatology.

Tethered cord syndrome (TCS) is a stretch-induced functional disorder of the spinal cord. The mechanical cause of TCS is an inelastic structure anchoring the caudal end of the spinal cord that prevents cephalad movement of the lumbosacral cord. Stretching of the spinal cord occurs in patients either when the spinal column grows faster than the spinal cord or when the spinal cord undergoes forcible flexion and extension. Research in patients and experimental animals suggests that there is a link between the clinical dysfunctions that characterize TCS and putative pathophysiological changes that accompany this syndrome. Among these changes are depression of electrophysiological activity and shifts in the reduction/oxidation ratio of cytochrome oxidase. The latter suggests that there is impairment of oxidative metabolism. These putative pathophysiological changes in TCS occur mainly within the lumbosacral cord under excessive tension. The authors discuss the pathophysiology of TCS and examine related symptoms.

Action Potentials↗

PubMedDate not supplied

[Attention deficit hyperactivity disorder. Cerebral asymmetry observed on magnetic resonance].

INTRODUCTION: Anatomical and functional neuroimaging data from subjects with Attention Deficit Hyperactivity Disorder (ADHD) have consistently implicated a reversal of cerebral asymmetry and suggested a fronto-striatal dysfunction in this disorder. OBJECTIVE: The aim of this study is to investigate the brain asymmetries in a homogeneous and non-medicated sample of adolescents with ADHD who had been previously studied in our laboratory. PATIENTS AND METHODS: T1-weighted magnetic resonance images were obtained for 11 adolescents with ADHD and 19 control subjects. Frontal and posterior brain regions, caudate nucleus, and ventricular system were quantitatively measured. RESULTS: A reversed pattern of asymmetry for the caudate nucleus (right > left) was found in ADHD when compared to the control group. We also found a reversed pattern of asymmetry for the frontal lobe (right < left) and a smaller right frontal volume (prefrontal specifically) in the ADHD subjects most severely impaired. Right caudate and frontal measures were inversely correlated. CONCLUSIONS: ADHD is associated with fronto-striatal abnormalities, which may be explicable via extant neurodevelopmental theories. Enlargement of the right caudate nucleus may suggest the failure of a process of synaptic 'pruning' by which attentional functions could be improperly transferred from the basal ganglia to frontal regions during development.

Adolescent↗

PubMed1992

Neuroactive kynurenines in Lyme borreliosis.

Although neurologic dysfunction occurs frequently in patients with Lyme borreliosis, it is rarely possible to demonstrate the causative organism within the neuraxis. This discordance could arise if neurologic symptoms were actually due to soluble neuromodulators produced in response to infection. Since immune stimulation is associated with the production of quinolinic acid (QUIN), an excitotoxin and N-methyl-D-aspartate (NMDA) agonist, we measured levels of CSF and serum QUIN, and lymphokines. Samples were obtained from 16 patients with CNS Borrelia burgdorferi infection, eight patients with Lyme encephalopathy (confusion without intra-CNS inflammation), and 45 controls. CSF QUIN was substantially elevated in patients with CNS Lyme and correlated strongly with CSF leukocytosis. In patients with encephalopathy, serum QUIN was elevated with corresponding increments in CSF QUIN. Lymphokine concentrations were not consistently elevated. We conclude that CSF QUIN is significantly elevated in B burgdorferi infection--dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA synaptic function--a receptor involved in learning, memory, and synaptic plasticity--may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients.

Brain Diseases↗