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PubMedDate not supplied

Evidence of a linkage between neurocardiogenic dysfunction and reactive hypoglycemia.

OBJECTIVE: Reactive hypoglycemia is a common medical problem whose pathophysiology is not completely understood. The objective of this study was to investigate the prevalence of autonomic nervous system abnormalities in patients with reactive hypoglycemia compared with controls. METHODS: Six women, mean age 31 +/- 5 years, with reactive hypoglycemia, and 5 healthy controls women aged 24 +/- 4 years were studied. We investigated the heart rate variability and blood pressure changes after an upright tilt with and without an isoproterenol infusion. A positive result was defined as syncope or presyncope associated with bradycardia, hypotension or both. RESULTS: In response to the orthostatic stress alone or in conjunction with a 4 micrograms isoproterenol infusion, 5 of 6 patients had a positive test as did one of the five control subjects. Patients had a baseline hyperadrenergic tone, with a sympathetic to parasympathetic ratio of 2.3 +/- 0.8 under basal conditions and 10.1 +/- 4.1 during the isoproterenol infusion, compared to 0.7 +/- 0.3 (p = 0.06) and 0.5 +/- 0.1 (p < 0.01) respectively, in the control group. CONCLUSION: Patients with reactive hypoglycemia may be at the extreme end of a spectrum of normal biologic variability, they may have an hyperadrenergic tone and, after a provocative stimulus, sympathetic nerve firing and or synaptic release of NE may not be sufficient to maintain an adequate vascular tone. Alternatively, the vascular response to NE may be impaired. An excessive and paradoxic vasovagal or parasympathetic response was not observed.

Adult↗

PubMed2005

Glial inflammation and neurodegeneration induced by candoxin, a novel neurotoxin from Bungarus candidus venom: global gene expression analysis using microarray.

Candoxin (PDB #1JGK), a three-finger neurotoxin from Bungarus candidus venom, inhibits post-synaptic neuromuscular and neuronal alpha7nACh-receptors, and induces delayed cell-death throughout the glial population. When applied to cultured human glial cell lines, candoxin (CDX) induced cell death in a concentration (EC(50) approximately 1muM) and time dependent manner. Results of TUNEL-histochemistry further confirm CDX-induced brain (hippocampus, frontal cortex, and temporal regions) damage when administered intracerebroventricularly (i.c.v) in adult mice. In this study, we explored differential gene expression profiles following exposure of human glial (Hs 683) cell lines to CDX at various time intervals using Affymetrix-GeneChips. By means of MAS and GeneSpring analyses, 105 genes whose expression was significantly (P<0.01) altered by at least 3-fold were selected. Results of the genome analysis reveal that the potential role of CDX at molecular level involves the regulation of genes in signal transduction, ubiquitin-inflammation, mitochondrial-dysfunction, and damage-response pathways. In addition, using QRT-PCR and rationally designed specific CDX-binding peptide (P-NT.II), we identified the genes-IL7R, IL13RA2, IL-1beta, TNFRSF12A, GADD45A, CD44 and IFI44-that might play an important role in CDX-induced glial inflammation, DNA-damage and degeneration. These findings reveal new insight into the molecular mechanisms of glial-driven neurodegeneration after exposure to neurotoxins.

Analysis of Variance↗

PubMed2002

A novel stereocilia defect in sensory hair cells of the deaf mouse mutant Tasmanian devil.

Stereocilia are specialized actin-filled, finger-like processes arrayed in rows of graded heights to form a crescent or W-shape on the apical surface of sensory hair cells. The stereocilia are deflected by the vibration of sound, which opens transduction channels and allows an influx of ions to depolarize the hair cell, in turn triggering synaptic activity. The specialized morphology and organization of the stereocilia bundle is crucial in the process of sensory transduction in the inner ear. However, we know little about the development of stereocilia in the mouse and few molecules that are involved in stereocilia maturation are known. We describe here a new mouse mutant with abnormal stereocilia development. The Tasmanian devil (tde) mouse mutation arose by insertional mutagenesis and has been mapped to the middle of chromosome 5. Homozygotes show head-tossing and circling and have raised thresholds for cochlear nerve responses to sound. The gross morphology of the inner ear was normal, but the stereocilia of cochlear and vestibular hair cells are abnormally thin, and they become progressively disorganized with increasing age. Ultimately, the hair cells die. This is the first report of a mutant showing thin stereocilia. The association of thin stereocilia with cochlear dysfunction emphasizes the critical role of stereocilia in auditory transduction, and the discovery of the Tasmanian devil mutant provides a resource for the identification of an essential molecule in hair cell function.

Action Potentials↗

PubMed2001

Ligand binding of the second PDZ domain regulates clustering of PSD-95 with the Kv1.4 potassium channel.

The molecular mechanisms underlying the protein assembly at synaptic junctions are thought to be important for neural functions. PSD-95, one of the major postsynaptic density proteins, is composed of three PDZ domains (PDZ1, PDZ2, and PDZ3), an SH3 domain, and a GK (guanylate kinase ) domain. It binds to the N-methyl-D-aspartate glutamate receptor NR2 subunit or to the Shaker-type K(+) channel, Kv1.4, via the PDZ1 or PDZ2 domain, whereas PDZ3 binds to distinct partners. The intramolecular interaction of these multiple domains has been implicated in efficient protein clustering. We introduced missense and deletion mutations into PDZ1 (PDZ1mDelta) and/or PDZ2 (PDZ2mDelta) of the full-length PSD-95 to disrupt the association of each domain with the target proteins, while preserving the overall structure. The ion channel clustering activities of the PSD-95 mutants were analyzed in COS-1 cells coexpressing each mutant and Kv1.4. The mutant bearing the dysfunctional PDZ2 (PSD-95:1-2mDelta) showed significantly reduced clustering efficiency, whereas the mutant with the dysfunctional PDZ1 (PSD-95:1mDelta-2) exhibited activity comparable with the wild-type activity. Furthermore, we also examined the requirements for the position of PDZ2 in full-length PSD-95 by constructing a series of PDZ1-PDZ2 inversion mutants. Surprisingly, the clustering activity of PSD-95:2-1mDelta was severely defective. Taken together, these findings show that PDZ2, which is endowed with the highest affinity for Kv1.4, is required for efficient ligand binding. In addition, the ligand binding at the position of the second PDZ domain in full-length PSD-95 is prerequisite for efficient and typical cluster formation. This study suggests that the correct placement of the multiple domains in the full-length PSD-95 protein is necessary for the optimal protein activity.

Amino Acid Sequence↗

PubMed1978

Contribution of trigeminal and facial reflexes to the localization of Vth, VIIth, and VIIIth cranial nerve dysfunction.

After a review of electrophysiological studies in 1,500 cases concerning different types of lesions of the trigeminal nerve, the acousticofacial complex, and the brain stem, one can conclude that beside the intensive clinical examination which most often allows a precise topographic diagnosis, study of trigeminofacial and facial reflexes appears to be an essential diagnostic method to determine the topography of the lesions. On the other hand, this study can sometimes contribute to the prognostic evaluation as well as the choice of the approach in some lesions concerning the acousticofacial complex.

Abducens Nerve↗

PubMed1998

Prolonged anoxic depolarization exacerbates NADH hyperoxidation and promotes poor electrical recovery after anoxia in hippocampal slices.

Mitochondrial dysfunction appears to occur during brain ischemia and following reperfusion. A characteristic event during reoxygenation after anoxia in hippocampal slices is hyperoxidation of the electron carriers of the mitochondrial respiratory chain. Earlier studies suggested that calcium influx due to loss of ion homeostasis during anoxia was linked to neuronal damage. Since a link between cytosolic calcium overload and post-anoxic hyperoxidation (PAMHo) has been suggested in previous studies, present studies sought to test the hypothesis that the length of anoxic depolarization can influence hyperoxidation and electrical activity recovery following anoxia in hippocampal slices. Rat hippocampal slices were made anoxic and then allowed to recover for 60 min. The time of anoxia was defined by the time of anoxic depolarization (AD), and slices were divided in five groups: 0.5, 1, 2, 5 and 10 min of AD. Reduction/oxidation shifts of NADH were measured by rapid scanning spectrofluorometry. Synaptic activity was indicated by population spike amplitudes in the CA1 pyramidal cell subfield of the hippocampus in response to stimulation of the Schaffer collaterals. We report here that mitochondrial hyperoxidation and synaptic activity in hippocampal slices are highly sensitive to the time in which slices remain depolarized (AD).

Animals↗

PubMed2005

Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways.

OBJECTIVE: To assess neurochemical deficits in patients with Parkinson disease (PD) associated dementia (PDD) in vivo. METHODS: The authors performed combined PET with N-[11C]-methyl-4-piperidyl acetate (MP4A) and 18F-fluorodopa (FDOPA) for evaluation of cholinergic and dopaminergic transmitter changes in 17 non-demented patients with PD and 10 patients with PDD. Data were compared to 31 age-matched controls by a combined region-of-interest and voxel-based Statistical Parametric Mapping analysis. RESULTS: The striatal FDOPA uptake was significantly decreased in PD and PDD without differences between the groups. The global cortical MP4A binding was severely reduced in PDD (29.7%, p < 0.001 vs controls) and moderately decreased in PD (10.7%, p < 0.01 vs controls). The PDD group had lower parietal MP4A uptake rates than did patients with PD. Frontal and temporo-parietal cortices showed a significant covariance of striatal FDOPA reduction and decreased MP4A binding in patients with PDD. CONCLUSIONS: While non-demented patients with Parkinson disease had a moderate cholinergic dysfunction, subjects with Parkinson disease associated dementia (PDD) presented with a severe cholinergic deficit in various cortical regions. The finding of a closely associated striatal FDOPA and cortical MP4A binding reduction suggests a common disease process leading to a complex transmitter deficiency syndrome in PDD.

Acetates↗

PubMed2005

N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease.

N-methyl-D-aspartate (NMDA) receptors are the major mediator of excitotoxicity. Although physiological activation of the NMDA receptor is necessary for cell survival, overactivation is a signal for cell death. Several pathways are activated through NMDA receptor stimulation, most of which can contribute to excitotoxicity. These include events leading to mitochondrial dysfunction, activation of calcium-dependent enzymes, and activation of mitogen-activated protein kinase pathways. Understanding the role of these mechanisms is important in developing agents that block excitotoxicity without inhibiting functions necessary for survival. NMDA receptor subtypes may be responsible for mediating separate pathways, and subtype-specific inhibition has shown promising results in some neurological models. This review examines the roles of NMDA receptor subtypes in excitotoxicity and neurological disorders.

Animals↗

PubMed1982

Colonic dysfunction in multiple sclerosis.

Multiple sclerosis is a central nervous system disease frequently accompanied by urinary symptoms and severe constipation. In order to investigate the pathophysiology of these symptoms, we studied colonic motor and myoelectrical activity, as well as colonic volume-pressure relationships (colonometrograms) and have correlated these data with cystometry and electrophysiologic studies of the central and peripheral somatosensory nervous system. The study group consisted of 7 patients with advanced multiple sclerosis marked by symptoms and signs of somatic and visceral nervous system dysfunction including severe constipation. Ten normal volunteers served as control subjects. The multiple sclerosis group demonstrated electrophysiologic evidence of lesions in the somatosensory neuroaxis central to the lumbosacral spinal cord. Abnormal cystometrograms suggested visceral central nervous system dysfunction. Colonometrograms in the multiple sclerosis group demonstrated a more rapid pressure rise than in the control group (p less than 0.01). The multiple sclerosis group failed to demonstrate the postprandial increase in colonic motor and myoelectrical activity observed in the control group (p less than 0.01). Abnormal colonometrograms and absent postprandial colonic motor and myoelectric responses may be features of visceral neuropathy in patients with advanced multiple sclerosis and severe constipation.

Colon↗

PubMed2005

Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs. Dominant mutations in the human SPG4 gene, encoding spastin, are responsible for the most frequent form of HSP. Spastin is an ATPase that binds microtubules and localizes to the spindle pole and distal axon in mammalian cell lines. Furthermore, its Drosophila homolog, Drosophila spastin (Dspastin), has been recently shown to regulate microtubule stability and synaptic function at the Drosophila larval neuromuscular junction. Here we report the generation of a spastin-linked HSP animal model and show that in Drosophila, neural knockdown of Dspastin and, conversely, neural overexpression of Dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease, including adult onset, locomotor impairment, and neurodegeneration. At the subcellular level, neuronal expression of both Dspastin RNA interference and mutant Dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse. In addition, we provide evidence that administration of the microtubule targeting drug vinblastine significantly attenuates these phenotypes in vivo. Our findings demonstrate that loss of spastin function elicits HSP-like phenotypes in Drosophila, provide novel insights into the molecular mechanism of spastin mutations, and raise the possibility that therapy with Vinca alkaloids may be efficacious in spastin-associated HSP and other disorders related to microtubule dysfunction.

Adenosine Triphosphatases↗

PubMedDate not supplied

Overexpression of a calcium-binding protein, S100 beta, in astrocytes alters synaptic plasticity and impairs spatial learning in transgenic mice.

Recent evidence suggests that slowly propagating Ca2+ waves from astrocytes can modulate the function of neurons. Altering astrocytic calcium processes in vivo may therefore affect neuronal and behavioral phenotypes. Previously, we generated transgenic mice that overexpress an astrocytic calcium-binding protein, S100 beta. Immunocytochemistry and in situ hybridization showed elevated expression in the astrocytes of the hippocampus and other brain regions. Neurons in the hippocampus were negative for S100 beta. In this paper we analyze the hippocampal electrophysiology and learning properties of mice from two transgenic lines. Significant differences were found between the hippocampal slices of normal and transgenic mice in their response to high frequency (100 Hz) stimulation. The overall distribution of post-tetanic excitatory postsynaptic potentials (EPSP) of the slices from the transgenic mice was shifted significantly toward smaller values to a degree that 25% of slices exhibited depression. The altered hippocampal neurophysiology was accompanied by an impairment in a hippocampal-dependent learning task. Transgenic mice showed significant impairment in a spatial version of the Morris water maze, however, they performed normally in non-spatial tasks. Probe trials showed that transgenic mice, though significantly impaired, also acquired spatial information. The results suggested that the impairment was not due to motor dysfunction, impaired vision or motivation of the transgenic mice, findings compatible with a possible hippocampal mechanism. We conclude that overexpression of S100 beta in astrocytes impairs, but does not abolish, the ability to solve a spatial task, and it leads to a significantly decreased post-tetanic potentiation in the hippocampal slice. We hypothesize that the changes are due to calcium mediated processes. Our results support the notion that astrocytes are involved in higher brain functions.

Animals↗

PubMedDate not supplied

The "Harlequin Sign". Case description and review of the literature.

Asymmetrical facial sweating and flushing has been named the "Harlequin Sign". This is a rare feature, as evident from only 12 cases described up to date. The "Harlequin Sign" represents a local autonomic dysfunction due to a cervical sympathetic deficit located at the pre or postganglionic level on the non-flushing side. We observed slow onset and progression of the "Harlequin Sign" in a 19-year-old man, with preexisting slight miosis on the non-flushing side. The differential diagnosis included other forms of dysautonomia and a secondary origin of this partial Horner's syndrome. Both pupils normally reacted to light, convergence, and pilocarpine eye-drop instillation, but the affected side showed supersensitivity to phenylephrine. Deep tendon reflexes were normal, thus excluding Adie's syndrome. The absence of cholinergic supersensitivity in the iris muscles indicated normal function of the ciliary ganglion and excluded the ocular parasympathetic deficit, also evident for the coexisting Horner's syndrome. The clinical features could be explained by assuming that the lesion was located at the level of postganglionic sympathetic fibers, probably due to trans-synaptic postganglionic neuronal degeneration at the level of the stellate ganglion, thus determining the onset of the hemifacial symptoms.

Adult↗

PubMed2006

Habenula lesions alter synaptic plasticity within the fimbria-accumbens pathway in the rat.

Both the habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the habenula produce disturbances of memory and attention in experimental animals. As the habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral habenula lesions on the plasticity of the fimbria-nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria-nucleus accumbens pathway is altered by habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the habenula is reported to exhibit exaggerated calcification.

Analysis of Variance↗

PubMed1985

Non-vascular central nervous system effects of calcium entry blockers.

Calcium entry blocker (CEB) use has been proposed in a variety of neurological dysfunctions. Some of the new clinical applications suggest a direct non-vascular action on neuronal activity. This view is supported by the observation that in brain CEBs bind preferentially to neuronal terminals and not to vascular elements. The data reported indicate that CEBs modify both in vitro and in vivo neurotransmitter release using brain slices and that their binding sites display some degree of plasticity in various experimental conditions altering neuronal transmission.

Age Factors↗

PubMed1999

Changes in synaptic expression of clathrin assembly protein AP180 in Alzheimer's disease analysed by immunohistochemistry.

Clathrin assembly protein AP180 plays a regulatory role in clathrin-mediated synaptic vesicle recycling in synapses. Previously, using immunoblot analysis, we observed a significant reduction of AP180 protein in Alzheimer's disease neocortex. In this study, we examined immunohistochemically the expression of AP180 in post mortem brains with Alzheimer's disease (n = 5) in comparison with neurologically normal controls (n = 5). Overall, AP180 was revealed as immunoreactive punctate granules located in the neuropil, and around neuronal cell bodies and their processes, consistent with the typical expression of synaptic proteins. Reduced density of AP180 immunoreactive puncta was seen throughout all layers of the superior frontal gyrus in Alzheimer's disease, but the loss of AP180 immunoreactivity was not as prominent in the cerebellum. This regional difference is in agreement with our previous results from immunoblot analyses. In the hippocampus, cell body AP180 immunoreactivity normally seen in the hilus and the CA3 regions of control brains was completely lost in Alzheimer's disease. In addition, AP180 immunoreactivity in the molecular layer of the dentate gyrus showed several changes in Alzheimer's disease. These appeared to be expansion of the inner molecular layer and relative changes in immunoreactivity that resulted in clearer delineation of the inner and outer molecular layers. These results provide anatomical and spatial information on AP180 expression in Alzheimer's disease brains. The variations in altered AP180 immunoreactivity in different brain regions of Alzheimer's disease may underlie the dysfunction of the corresponding synapses.

Adaptor Proteins, Vesicular Transport↗

PubMed1999

GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization.

GABAB (gamma-aminobutyric acid)-receptors have been implicated in central nervous system (CNS) functions, e.g. cognition and pain perception, and dysfunctions including spasticity and absence epilepsy. To permit an analysis of the two known GABAB-receptor splice variants GABAB-R1a (GB1a) and GABAB-R1b (GB1b), their distribution pattern has been differentiated in the rat brain, using Western blotting and immunohistochemistry with isoform-specific antisera. During postnatal maturation, the expression of the two splice variants was differentially regulated with GB1a being preponderant at birth. In adult brain, GB1b-immunoreactivity (-IR) was predominant, and the two isoforms largely accounted for the pattern of GABAB-receptor binding sites in the brain. Receptor heterogeneity was pronounced in the hippocampus, where both isoforms occurred in CA1, but only GB1b in CA3. Similarly, in the cerebellum, GB1b was exclusively found in Purkinje cells in a zebrin-like pattern. The staining was most pronounced in Purkinje cell dendrites and spines. Using electron microscopy, over 80% of the spine profiles in which a synaptic contact with a parallel fibre was visible contained GB1b-IR at extrasynaptic sites. This subcellular localization is unrelated to GABAergic inputs, indicating that the role of GABAB-receptors in vivo extends beyond synaptic GABAergic neurotransmission and may, in the cerebellum, involve taurine as a ligand.

Animals↗

PubMed2002

Aging and surface expression of hippocampal NMDA receptors.

Aging is known to alter many physiological processes within the brain including synaptic responses, long-term potentiation, learning, and memory. Aging has also been shown to alter the expression and distribution of N-methyl-d-aspartate (NMDA) receptors in many different brain regions, including the hippocampus. Additionally, we have recently reported that young adult rats show an activity-dependent increase in the surface expression of NMDA receptors. We have extended these observations in the present study in aged animals and have found that aged Fischer 344 rats fail to show activity-dependent changes in the surface distribution of NMDA receptors. In conjunction with this observation we have also noted that aged rats show an expression deficit in the C2 splice variant of the NR1 subunit. This subunit is preferentially shifted to the surface following stimulation in young adult animals. As the NMDA receptor is thought to play an important role in neuronal signaling, these observations suggest possible new areas of dysfunction in this receptor that might underlie age-related deficits in neuronal physiology.

Aging↗

PubMed2006

Neurosteroid modulation of respiratory rhythm in rats during the perinatal period.

Neurosteroids regulate neuronal excitability and are expressed at particularly high levels in the CNS during the perinatal period. Further, neurosteroid levels are increased by a variety of stressors including hypoxia, asphyxia, parturition, ethanol exposure and infection. One mechanism by which neurosteroids regulate neuronal activity is by negative or positive modulation of GABA(A) receptor function. Perinatal respiration is strongly modulated by GABAergic synaptic drive, and GABA release is increased during hypoxia to contribute to hypoxia-induced depression of neonatal ventilation. Here, we use in vitro and in vivo rat models to test the hypothesis that GABA(A) receptor-mediated modulation of perinatal respiration is markedly influenced by the presence of neurosteroids. The principal finding of this study was that the efficacy of GABA(A) receptor-mediated modulation of respiratory membrane potential and rhythmogenesis is markedly enhanced by allopregnanolone and depressed by dehydroepiandrosterone sulphate. These data demonstrate that the modulation of breathing via GABA(A) receptor activation will be determined by the overall balance of negative and positive neurosteroid modulators within respiratory nuclei. This adds a level of complexity that must be considered when examining the depression of breathing in mammals associated with various behavioural states and pathogenic conditions such as apnoea and sudden death suspected to be associated with central respiratory dysfunction.

Action Potentials↗