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Convulsive manifestations are synchronized mass-discharges which are caused by a dysfunction of the dynamic equilibrium between excitation and inhibition. This is caused by a change in membrane activity which increases or decreases the effectiveness of neurotransmitters. We showed the effect of ions on membrane activity and epileptic discharges.
The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation-contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle.
Over the last 15 years, neurobiologists have begun to unravel the cellular mechanisms that underlie epileptiform activity. Such investigations have two main objectives: (1) to develop new methods for treating, "curing," or preventing epilepsy: and (2) to learn more about the normal functioning of the human brain, at the cellular/molecular and the neurological/psychological levels by analyzing abnormal brain functioning. The electroencephalogram (EEG) spike is a marker for the hyperexcitable cortex and arises in or near an area with a high epileptogenic potential. The depolarizing shift (DS) that underlies the interictal discharge (ID) appears to be generated by a combination of excitatory synaptic currents and intrinsic voltage-dependent membrane currents. The hyperpolarization that follows the DS (post-DS HP) limits ID duration, determines ID frequency, and prevents ID deterioration into seizures. The disappearance of the post-DS HP in some models is related to the onset of seizures and the spread of epileptiform activity. During the transition to seizures, the usually self-limited ID spreads in time and anatomical space. Several processes may intervene in the pathophysiological dysfunction. These include enhancing GABA-mediated inhibition, dampening NMDA-mediated excitability, interfering with specific Ca2+ currents in central neurons, and perhaps stimulating "gating" pathways.
OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of parasympathetic neurotransmission may contribute to the glandular dysfunction. In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. METHODS: Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG. RESULTS: Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by approximately 50%. Sera from these patients also inhibited the action of neuronally released acetylcholine at M3-muscarinic receptors. Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist- and nerve-evoked contractions. In this preliminary study, the autoantibodies seemed to be associated with the presence of bladder symptoms and other autonomic features. CONCLUSION: Autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS. Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS. These autoantibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfunction in some patients.
BACKGROUND: Impaired smooth muscle contractility is important in the pathophysiology of acalculous cholecystitis. Common bile duct ligation (CBDL) is a model of acalculous cholecystitis, producing acute inflammatory changes and decrease in gallbladder smooth muscle contractility. The aim of this study was to determine whether there is coexistent dysfunction of neural efferent motor pathways of the gallbladder after CBDL. MATERIALS AND METHODS: Gallbladder muscle contractility was studied in vitro in normal, CBDL, and sham-operated guinea pigs. Electric field stimulation (EFS; 2-16 Hz) was used to activate intrinsic nerves and exogenous acetylcholine (ACh) was used to directly stimulate the muscle. H&E-stained slides of muscle strips were scored for inflammatory changes. RESULTS: After CBDL, there was a progressive increase in the inflammation score and decrease in gallbladder muscle contractility to ACh. There was also a progressive decline in EFS-induced contractility when expressed as absolute force or normalized to the maximal muscle contractile response to ACh. The nitric oxide synthase inhibitor l-NNA (10 microM) increased EFS-induced contractions by 50 +/- 25% (P = 0.05) in CBDL animals but had no effect in sham surgical controls. CONCLUSIONS: CBDL with its acute gallbladder inflammation affects gallbladder contractility by two mechanisms: (1) decreased smooth muscle contractility, and (2) decreased neurally mediated contractions. The neurally mediated alterations result from dysfunction of cholinergic excitatory nerves and upregulation of nitric-oxide-mediated inhibition of smooth muscle contractility.
1. The electrical field stimulation (EFS)-induced bronchoconstriction in vitro in rats challenged by DNP-Ascaris antigen was significantly greater than that in normal rats. 2. Morphine inhibited the EFS-induced bronchoconstriction in normal rats. Whereas the inhibition of EFS-induced bronchoconstriction by the opioid was little, if any, in the DNP-Ascaris-challenged rats. 3. These findings suggest that dysfunction of presynaptic inhibitory modulation through the opioid receptor may take place in the airways of DNP-Ascaris-challenged rats.
Depressive-like behavior is the most profound manifestation of autoimmunity-associated behavioral syndrome in lupus-prone MRL-lpr mice. This led to the hypothesis that chronic autoimmunity and inflammation alter the activity of central serotonergic and dopaminergic systems. Three drugs with a selective mode of action were used to probe the functional status of these two systems in vivo. The behavioral effects of single and repeated intraperitoneal (i.p.) injections of sertraline, quinpirole (QNP) and risperidone were measured in the forced swim and brief sucrose preference tests. In comparison to MRL +/+ controls, autoimmune MRL-lpr mice did not show a reduction in sucrose intake after the administration of sertraline. Acute injection of quinpirole increased floating more in the MRL-lpr than in the control group, while intermittent administration induced self-injurious behavior in both groups. Acute injection of risperidone significantly increased floating in MRL-lpr mice, while repeated administration abolished the difference between the substrains in sucrose intake. These discrepancies in responsiveness implied that the central neurotransmitter activity is dissimilar in the two MRL substrains. This notion was confirmed in a cohort of untreated MRL-lpr and MRL +/+ mice by comparing their neurotransmitter/metabolite levels in several brain regions. In particular, MRL-lpr brains showed increased dopamine (DA) levels in the paraventricular nucleus (PVN) and median eminence (ME), decreased concentrations of serotonin in the PVN and enhanced levels in the hippocampus, as well as decreased norepinephrine (NE) levels in the prefrontal cortex. Behavioral deficits correlated with the changes in PVN and median eminence. These results are consistent with the hypothesis that imbalanced neurotransmitter regulation of the hypothalamus-pituitary axis plays an important role in the etiology of behavioral dysfunction induced by systemic autoimmune disease.
Increased serotonergic activity is discussed as an important pathogenetic factor in schizophrenia. Further support for this hypothesis is difficult to obtain due to the lack of valid indicators of the brain's serotonin system. A great deal of evidence discovered through human and animal studies suggests that a weak loudness dependence of auditory evoked potentials (LDAEP) indicates high serotonergic activity and vice versa. The LDAEP is a measure of auditory cortex activity, reflecting increase or decrease of auditory evoked potential amplitudes with increasing tone loudness, which is probably modulated by the serotonergic innervation there. This is true only for the LDAEP of the primary auditory cortex, since this region is more highly innervated by serotonergic fibers than the secondary auditory cortex. The LDAEP (N1/P2 component) of 25 inpatients with schizophrenia free of medication and 25 healthy controls matched by age and gender, were recorded. Using dipole source analysis, the LDAEP of primary (tangential dipole) and this of secondary auditory cortex (radial dipole) was separately analyzed. Following a 4-week treatment with the 5-HT(2) antagonists clozapine or olanzapine, patients were once again studied. The LDAEP of the primary, but not of the secondary auditory cortex, was significantly weaker in the patients with schizophrenia than in healthy volunteers, indicating enhanced serotonergic neurotransmission. After treatment with the 5-HT(2) antagonists, the LDAEP (of the right hemisphere) tended to be increased, indicating normalization of serotonergic function in the patients with schizophrenia. These results suggest that the loudness dependence of primary auditory cortex evoked activity is well suitable to assess serotonergic dysfunction in schizophrenia.
OBJECTIVE: Within the prefrontal cortex of schizophrenic subjects, alterations in markers of gamma-aminobutyric acid (GABA) neurotransmission, including decreased immunoreactivity for the GABA membrane transporter GAT-1, may be most prominent in a subset of inhibitory neurons. In the present study, the authors sought to determine whether the alterations in GAT-1 protein could be attributed to a reduction in GAT-1 mRNA expression. METHOD: Tissue sections containing prefrontal cortex area 9 from 10 matched pairs of schizophrenic and comparison subjects were processed for in situ hybridization histochemistry with (35)S-oligonucleotide probes for GAT-1 mRNA. RESULTS: In the schizophrenic subjects, the relative density of labeled neurons was 21%-33% lower in layers 1-5 of the prefrontal cortex but was unchanged in layer 6. In contrast, cellular levels of GAT-1 mRNA expression, as reflected in grain density per labeled neuron, did not differ by more than 11% between subject groups in any layer. These findings indicate that GAT-1 mRNA expression is relatively unaltered in the majority of prefrontal cortex GABA neurons in schizophrenic subjects but is reduced below a detectable level in a subset of GABA neurons. Furthermore, the magnitude and laminar pattern of these results were strikingly similar to those found in a previous study of mRNA expression for the synthesizing enzyme of GABA, glutamic acid decarboxylase(67), in the same subjects. CONCLUSIONS: Both GABA synthesis and reuptake appear to be altered at the level of gene expression in a subset of GABA neurons, and the resulting changes in GABA neurotransmission may contribute to prefrontal cortex dysfunction in schizophrenia.
Positron emission tomography (PET) is a functional imaging technique which allows detection of biochemical and pharmacological dysfunction of the nigrostriatal dopaminergic system and provides the opportunity to investigate living patients with PD. This paper reviews the contribution of PET studies to the understanding of neurochemical changes underlying Parkinson's disease.
In mice whose Gi/o-protein function had been impaired by antisense 'knock-down' or pertussis toxin treatment, i.c.v. injection of myr+-Gi/o alpha subunits restored the effectiveness of beta-endorphin, morphine, DPDPE, clonidine and neurotensin to produce antinociception. Myr+-G alpha subunits of the class of G-proteins actually impaired were more effective than unlike but related myr+-G alpha subunits. Selectivity was noted in that only exogenous myr+-G alpha subunits affected (enhanced) the activity of agonists in G alpha-deficient signalling systems. This treatment had little effect on agonist potency when the impairment resided at the receptor level. The potential of the opioids, clonidine and R-PIA to increase G alpha-related in vitro hydrolysis of GTP was also re-established after injecting myr+-Gi2 alpha subunits into Gi2-knocked-down mice. Myr+-Gi2 alpha subunits pre-incubated with GTPgammaS or GDPbetaS before i.c.v. injection did not improve the activity of agonists in vivo (antinociception) or in vitro (regulation of low Km GTPase). After impairing the function of PKCbeta1 by antisense treatment or with the inhibitor H7, the effect of myr+-G alpha subunits on agonist potency was prevented. Electron microscope analysis showed the entry of gold-conjugated myr+-G alpha subunits into neural cells. These particles were found in the cytoplasm, associated with the plasma membranes of different neuronal processes and also in synaptic junctions. In cultured neurons and astrocytes myr+-Gi2 alpha-associated fluorescence was internalised in a dose-dependent manner and distributed in the plasma membrane and cytosol, as well as in nuclei of dividing astrocytes. Thus, G alpha subunits in CSF enter into neurons and functionally couple to the receptor-triggered signalling cascade. As G-proteins have been implicated in the pathophysiology of several neural disorders, this finding may be valuable in the therapy of such dysfunctions.
The role of central serotonergic (5-HT) system dysfunction in the regulation of aggression in both animals and man has been investigated for more than the past two decades. Evidence for reduced central 5-HT in the mediation of aggression comes from both behavioural and correlative studies. Functional reduction and augmentation of 5-HT activity is respectively associated with increased and decreased aggression in various animal models of aggression. While similar studies in man have not been performed, strong and consistent associations between indices reflecting reduced pre-synaptic 5-HT activity and aggression have been reported. Evidence of post-synaptic receptor upregulation in the brains of suicide victims has also been reported leaving the functional status 5-HT activity in such patients an open question. However, reduced neuroendocrine (i.e. prolactin) responses to fenfluramine, a 5-HT uptake inhibitor/releaser, which activates both pre- and post-synaptic sides of the 5-HT synapse, strongly suggest that overall central 5-HT activity is reduced in mood and/or personality disorder patients with history of suicidal and/or impulsive aggressive behaviour. Preliminary data with the 5-HT receptor agonist m-chlorophenylpiperazine further suggest that reduced activity of post-synaptic 5-HT receptors may be an important correlate of impulsive aggressive behaviour. Pharmacological agents with potent 5-HT pre- and/or post-synaptic augmenting effects should be tested clinically to determine their efficacy in the treatment of impulsive aggressive behaviour in psychiatric patients.
The afferent synapse between the auditory nerve fiber and the inner hair cell (IHC) represents a critical junction for hearing. Elucidation of the structure at this site will help establish the substrate for normal sound encoding as well as pathologic processes associated with hearing dysfunction. Previous applications of unbiased (design-based) stereological principles have expanded our knowledge of neuro-morphological changes evident with the light microscope. Applying these principles at the level of the synapse is a promising morphometric approach for the efficient sampling of large reference spaces with electron microscopy. This study tests the accuracy of using ultra-thin sections at a fixed interval, known as disector pairs, to quantify afferent innervation density. We analyzed the total numbers of afferent terminals, synaptic thickenings, and synaptic bodies associated with each IHC in the C57BL/6J mouse cochlea, and confirmed the accuracy of the stereological approach in comparison to three-dimensional reconstructions of serial alternate sections. The higher sampling efficiency of the disector pair method rapidly increases precision while also reducing the largest source of variability, inter-animal differences. We conclude that ultrastructural quantification of afferent innervation can be accomplished in the cochlea using efficient design-based stereology.
This article argues how dopamine controls working memory and how the dysregulation of the dopaminergic system is related to schizophrenia. In the dorsolateral prefrontal cortex, which is the principal part of the working memory system, recurrent excitation is subtly balanced with intracortical inhibition. A potent controller of the dorsolateral prefrontal cortical circuit is the mesocortical dopaminergic system. To understand the characteristics of the dopaminergic control of working memory, the stability of the circuit dynamics under the influence of dopamine has been studied. Recent computational studies suggest that the hyperdopaminergic state is usually stable but the hypodopaminergic state tends to be unstable. The stability also depends on the efficacy of the glutamatergic transmission in the corticomesencephalic projections to dopamine neurons. When this cortical feedback is hypoglutamatergic, the circuit of the dorsolateral prefrontal cortex tends to be unstable, such that a slight increase in dopamine releasability causes a catastrophic jump of the dorsolateral prefrontal cortex activity from a low to a high level. This may account for the seemingly paradoxical overactivation of the dorsolateral prefrontal cortex observed in schizophrenic patients. Given that dopamine transmission is abnormal in the brains of patients with schizophrenia and working memory deficit is a core dysfunction in schizophrenia, the concept of circuit stability would be useful not only for understanding the mechanisms of working memory processing but for developing therapeutic strategies to enhance cognitive functions in schizophrenia.
Ionotropic glutamate receptors (iGluRs) mediate excitatory synaptic transmission in vertebrates and invertebrates through ligand-induced opening of transmembrane ion channels. iGluRs are segregated into three subtypes according to their sensitivity to the agonists AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), kainate (a structural analogue of glutamate) or NMDA (N-methyl-D-aspartate). iGluRs are important in the development and function of the nervous system, are essential in memory and learning, and are either implicated in or have causal roles in dysfunctions ranging from Alzheimer's, Parkinson's and Huntington's diseases, schizophrenia, epilepsy and Rasmussen's encephalitis to stroke. Development of iGluR agonists and antagonists has been hampered by a lack of high-resolution structural information. Here we describe the crystal structure of an iGluR ligand-binding region in a complex with the neurotoxin (agonist) kainate. The bilobed structure shows the determinants of receptor-agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond. The structure indicates mechanisms for allosteric effector action and for ligand-induced channel gating. The information provided by this structure will be essential in designing new ligands.
OBJECTIVE: To identify and investigate any dysfunction of neuromuscular transmission in episodic cluster headache. BACKGROUND: Abnormal neuromuscular transmission has been shown in migraine with aura and in migraine without aura by using single fiber electromyography. Especially for migraine with aura, a genetic cause has been postulated. Episodic cluster headache is a primary headache disorder in which genetic factors may, at times, play a strong role. METHODS: Single fiber electromyography during voluntary contraction of the extensor digitorum communis muscle, nerve conduction studies of upper and lower extremities, and concentric needle electromyography of the extensor digitorum communis were performed on 6 patients with episodic cluster headache and 6 age-matched normal controls. Twenty potential pairs were recorded from each subject. Twenty individual jitter values and a mean jitter value were calculated for each subject. Both mean individual jitter values and numbers of abnormal individual jitter values were compared in patients with cluster headache versus normal controls. RESULTS: Three of 6 patients with episodic cluster headache showed pronounced neuromuscular transmission abnormalities by single fiber electromyography. None of the controls had any neuromuscular transmission abnormality. Another patient with episodic cluster headache had borderline dysfunction of neuromuscular transmission. Transmission was clearly normal in only 2 of 6 patients with cluster headache. CONCLUSION: These results suggest that episodic cluster headache may share the same abnormality of neuromuscular transmission observed in migraine.
Bardet-Biedl syndrome (BBS) and Usher syndrome (USH) are the most prevalent syndromic forms of retinitis pigmentosa (RP), together they make up almost a quarter of the patients with RP. BBS is defined by the association of retinopathy, obesity, hypogonadism, renal dysfunction, postaxial polydactyly and mental retardation. This clinically complex syndrome is genetically heterogeneous with linkage to more than 6 loci, and 4 genes have been cloned so far. Recent molecular data present evidence that, in some instances, the clinical manifestation of BBS requires recessive mutations in 1 of the 6 BBS loci plus one or two additional mutations in a second BBS locus (tri- or tetra-allelic inheritance). USH is characterized by the combination of congenital or early-onset sensorineural deafness, RP, and variable degrees of vestibular dysfunction. Each of the three clinical types is genetically heterogeneous: 7 loci have been mapped for type 1, three loci for type 2, and two loci for type 3. Currently, 6 USH genes (MYO7A, USH1C, CDH23, PCDH15, USH2A, USH3) have been identified. Pathogenetically, mutations of the USH1 genes seem to result in defects of auditory and retinal sensory cells, the USH 2 phenotype is caused by defects of extracellular matrix or cell surface receptor proteins, and USH3 may be due to synaptic disturbances. The considerable contribution of syndromic forms of RP requires interdisciplinary approaches to the clinical and diagnostic management of RP patients.
The deleterious effects of Carbon Tetrachloride, widely used industrially, on the peripheral nervous system was investigated by experimentation on rabbits. Long-term infusion simulated various conditions of exposure to obtain pharmacological and electroneurographic data. Tetrachlorethen is shown to induce reversible dysfunctions of the peripheral nervous system depending on the degree of concentration. The mode of molecular action remains open. Our results are compared with references in existing literature.