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PubMed1987

[Mechanisms of functional disorders of the autonomic nervous system in Lambert-Eaton myasthenic syndrome].

The authors have examined the status of sympathetic innervation of the skin structures (by measuring the amplitude and latent period of the appearance of the evoked skin sympathetic potential, ESSP) and the autonomic regulation of the cardiovascular system (by examining the R-R intervals of the ECG at rest and in various functional tests) in 9 patients with the Lambert-Eaton myasthenic syndrome, 10 normal subjects, and in 20 myasthenic patients (a control group). All patients examined before the treatment and 7 patients who were examined following the administration of corticosteroid therapy presented disorders of the latent period and/or the amplitude of ESSP, up to its total absence, as well as signs of cardiac arrhythmias indicative of a marked dysfunction of the cholinergic structures of the peripheral nerves. No correlation has been elicited between the depth of identified vegetative disturbances and the presence of clinical and electromyographic indicators of polyneuropathy. Medicamentous tests serve to confirm the synaptic nature of cholinergic disorders.

Autonomic Nervous System↗
PubMed1999

Oxygen/glucose deprivation in hippocampal slices: altered intraneuronal elemental composition predicts structural and functional damage.

Effects of oxygen/glucose deprivation (OGD) on subcellular elemental composition and water content were determined in nerve cell bodies from CA1 areas of rat hippocampal slices. Electron probe x-ray microanalysis was used to measure percentage water and concentrations of Na, P, K, Cl, Mg, and Ca in cytoplasm, nucleus, and mitochondria of cells exposed to normal and oxygen/glucose deficient medium. As an early (2 min) consequence of OGD, evoked synaptic potentials were lost, and K, Cl, P, and Mg concentrations decreased significantly in all morphological compartments. As exposure to in vitro OGD continued, a negative DC shift in interstitial voltage occurred ( approximately 5 min), whereas general elemental disruption worsened in cytoplasm and nucleus (5-42 min). Similar elemental changes were noted in mitochondria, except that Ca levels increased during the first 5 min of OGD and then decreased over the remaining experimental period (12-42 min). Compartmental water content decreased early (2 min), returned to control after 12 min of OGD, and then exceeded control levels at 42 min. After OGD (12 min), perfusion of hippocampal slices with control oxygenated solutions (reoxygenation) for 30 min did not restore synaptic function or improve disrupted elemental composition. Notably, reoxygenated CA1 cell compartments exhibited significantly elevated Ca levels relative to those associated with 42 min of OGD. When slices were incubated at 31 degreesC (hypothermia) during OGD/reoxygenation, neuronal dysfunction and elemental deregulation were minimal. Results show that in vitro OGD causes loss of transmembrane Na, K, and Ca gradients in CA1 neurons of hippocampal slices and that hypothermia can obtund this damaging process and preserve neuronal function.

Animals↗
PubMed2005

alpha7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in beta-amyloid infused rats.

Continuous intracerebroventricular infusion of beta-amyloid peptide 1-40 (Abeta(1-40)) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itoh, A., Hasegawa, T., Nabeshima, T., 1994. Beta-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63-66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral-CA1 synapse in hippocampal slices from Abeta-infused brain. Throughout this study, an effort was made to address whether the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), which is believed to be a primary target of Abeta [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Abeta (1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155-1161.], is responsible for the deficits in synaptic plasticity observed in the Abeta-infused rats. First, we found that Abeta-infusion markedly depressed the response of alpha7nAChR to a selective alpha7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of alpha7nAChR with either methyllycaconitine (MLA) or alpha-bungarotoxin (alpha-BTX) in control rats inhibited LTP induction, suggesting that the activation of alpha7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Abeta-infused rats with 10 microM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Abeta-impaired LTP and PPF arise as a consequence of dysfunctional alpha7nAChR, and that alpha7nAChR may be an important target to help ameliorate AD patient cognitive deficits.

Amyloid beta-Peptides↗
PubMed1986

Reduced responsiveness of locus coeruleus neurons to cutaneous thermal stimuli in capsaicin-treated rats.

Recent electrophysiological experiments have shown that brain norepinephrine (NE) neurons in the locus coeruleus (LC) are activated by cutaneous thermal stimuli of both non-noxious and noxious character. In the present study the LC neuronal response to thermal stimuli was used to evaluate cutaneous thermal sensitivity in capsaicin-treated rats, a treatment that is described to cause impaired thermoregulation. Capsaicin treatment, of neonates as well as of adult rats, caused a reduced responsiveness of brain LC neurons to thermal stimuli. The results suggest that a reduction in peripheral thermal afferent transmission may be one mechanism underlying the capsaicin-induced thermoregulatory dysfunction.

Age Factors↗
PubMedDate not supplied

Cannabinoid receptors and their ligands.

There are at least two types of cannabinoid receptors, CB(1) and CB(2), both coupled to G proteins. CB(1) receptors exist primarily on central and peripheral neurons, one of their functions being to modulate neurotransmitter release. CB(2) receptors are present mainly on immune cells. Their roles are proving more difficult to establish but seem to include the modulation of cytokine release. Endogenous agonists for cannabinoid receptors (endocannabinoids) have also been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether. Other endocannabinoids and cannabinoid receptor types may also exist. Although anandamide can act through CB(1) and CB(2) receptors, it is also a vanilloid receptor agonist and some of its metabolites may possess yet other important modes of action. The discovery of the system of cannabinoid receptors and endocannabinoids that constitutes the "endocannabinoid system" has prompted the development of CB(1)- and CB(2)-selective agonists and antagonists/inverse agonists. CB(1)/CB(2) agonists are already used clinically, as anti-emetics or to stimulate appetite. Potential therapeutic uses of cannabinoid receptor agonists include the management of multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, vasodilation that accompanies advanced cirrhosis, and cancer. Following their release onto cannabinoid receptors, endocannabinoids are removed from the extracellular space by membrane transport and then degraded by intracellular enzymic hydrolysis. Inhibitors of both these processes have been developed. Such inhibitors have therapeutic potential as animal data suggest that released endocannabinoids mediate reductions both in inflammatory pain and in the spasticity and tremor of multiple sclerosis. So too have CB(1) receptor antagonists, for example for the suppression of appetite and the management of cognitive dysfunction or schizophrenia.

Animals↗
PubMed2025

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

BACKGROUND: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups. CONCLUSIONS: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Humans↗
PubMed2002

Functional domains in dorsal striatum of the nonhuman primate are defined by the dynamic behavior of dopamine.

The dorsal striatum comprises a continuum of distinct functional domains, limbic, associative, and sensorimotor. In the primate it exclusively subdivides further into two nuclei, the putamen and caudate. Dopamine (DA) transmission is differentially affected between these nuclei in neurodegenerative diseases such as Parkinson's and by psychostimulants such as cocaine. Because rodent systems can offer only limited insight into DA systems of the human brain, a fuller appreciation of DA transmission and its role in dysfunction requires direct study in primates. DA behavior was explored in the major functional domains of the caudate nucleus and compared with the putamen, using fast-scan cyclic voltammetry in striatal sections from the marmoset (Callithrix jacchus). There was domain-specific variation in extracellular DA transients [i.e., concentration ([DA](o)) released by a single stimulus and the rate maximum of DA uptake, V(max)]. Across nuclei, functional rather than anatomical regions were differentiated by these dynamics. The largest, fastest DA transients were at motor-associated loci. Evoked [DA](o) at physiological frequencies was differently frequency-sensitive between functional domains but not between anatomical nuclei. In contrast, presynaptic depression was not an index of regional differentiation, recovering with similar kinetics at all loci. Within a given functional domain of dorsal striatum, the dynamics of DA release and uptake are similar for the putamen and the caudate nucleus. Conversely, distinct functional domains are defined by these DA dynamics, in a manner more marked in primates than in rodents. These data from the primate brain highlight differences in DA availability that may be central to DA function and dysfunction in the human.

Animals↗
PubMed1995

Receptors, photoreception and brain perception. New insights.

Once photons have activated photosensitive cell receptors, a biochemical process mediated by G-proteins transforms the initial signal into nerve potentials. The generated impulses transmit the information through ganglion cells, after a complex interaction with other neurons by means of different neurotransmitters. Since visual function is processed in parallel, ganglion cells are divided into M-neurons which are in charge of capturing large objects, P-neurons capable of analyzing fine details and colors, and non-M, non-P neurons which are sensitive to changes in light intensity. Retina, bipolar and ganglion cells share circular receptive fields with an antagonistic surround whereas the lateral geniculate nucleus possesses rectangular receptive fields. Thus, when central cones are stimulated, ON-center cells depolarize, while OFF-center cells hyperpolarize. At the brain cortex, the magnocellular layers lead to orientation and achromatic perception, the parvocellular layers perform color vision in the blobs and achromatic contrast and orientation in the interblobs, and eventually, binocular perception is the result of multiple disparities phenomenon. On these bases, patients with agnosia for form and pattern or for depth and movement have been described. Likewise, color blindness is another disease that could be the result of photoreceptor dysfunctions or brain perception defects.

Animals↗
PubMed1999

Biochemical dysfunction and memory loss: the case of Alzheimer's dementia.

Among the different types of cognitive impairment that appear with increasing age, Alzheimer's disease (AD) is rated as the most frequent. Despite intensive research, key questions concerning AD aetiology remain elusive, but it appears that many biochemical events crucial for neuronal communication and synaptic plasticity fail during the course of the disease. The aim of this review is therefore to provide an overview of intracellular cascades involved in AD pathology. For almost all factors. it is a matter of controversy whether their contribution should be considered to be cause or effect. However, intracellular signalling may be crucial as it is in learning and memory mechanisms and malfunction of biochemical pathways may be a common denominator in neurodegenerative processes, thus providing new venues for treatment and therapeutic strategies.

Alzheimer Disease↗
PubMed1998

Inhibition of Na+,K+-ATPase from rat brain cortex by propionic acid.

Buffered propionic acid was injected s.c. into rats twice a day at 8 h intervals from the 6 to 21 days of age. Control rats received saline in the same volumes. The animals were weighed and killed by decapitation at 23 days. Whole brain and cerebral cortex were weighed and synaptic plasma membranes were prepared from cortex for the determination of Na+,K+-ATPase and Mg2+-ATPase activities. Body, whole brain and cortical weights were similar in the two groups, suggesting that propionic acid does not cause malnutrition in rats. Na+,K+-ATPase activity was significantly reduced by 30% in membranes from the propionate-treated group, whereas Mg2+-ATPase activity was not. In another set of experiments, synaptic plasma membranes were prepared from cerebral cortex of 23-day-old rats and incubated with propionic acid at final concentrations ranging from 0.1 to 2.0 mM. Na+,K+-ATPase activity, but not Mg2+-ATPase activity, was inhibited by 22-32%. Since propionic acid concentrations in plasma of chronically treated rats and of propionic acidemic children are of the same order of magnitude as those tested in vitro, the results suggest that the inhibition of Na+,K+-ATPase activity may be related to the neurological dysfunction of patients affected by propionic acidaemia.

Animals↗
PubMed1989

Delayed onset of distal axonal neuropathy in primates after prolonged low-level administration of a neurotoxin.

Short-latency somatosensory evoked potentials were recorded from surface electrodes overlying peripheral nerve, spinal cord, and cortex in 4 monkeys during prolonged intoxication with low levels of acrylamide. A fifth animal served as a longitudinal control subject. Slowing of the response across the spinal-medullary junction was a reliable sign, manifest only after prolonged exposure. Associated morphological changes were preterminal accumulation of axonal neurofilaments without synaptic disruption in the gracile nucleus. The induced alterations in the latency of short-latency somatosensory evoked potentials and in axon morphology were reversible after 7 months of recovery. The extreme delay in onset of subtle neurological dysfunction (940 days) following administration of a presumed safe level of acrylamide suggests that permissible levels of human exposure to toxins of this type should be reassessed.

Acrylamide↗
PubMed2005

Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.

Na+/Cl--dependent transporters terminate synaptic transmission by using electrochemical gradients to drive the uptake of neurotransmitters, including the biogenic amines, from the synapse to the cytoplasm of neurons and glia. These transporters are the targets of therapeutic and illicit compounds, and their dysfunction has been implicated in multiple diseases of the nervous system. Here we present the crystal structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions. The protein core consists of the first ten of twelve transmembrane segments, with segments 1-5 related to 6-10 by a pseudo-two-fold axis in the membrane plane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The structure reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates.

Amino Acid Sequence↗
PubMed2003

Novel modulatory mechanisms revealed by the sustained application of nicotine in the guinea-pig hippocampus in vitro.

The alpha 7 nicotinic acetylcholine receptor (nAChR) has been implicated widely in behavioural functions and dysfunctions related to the hippocampus, but the detailed mechanisms by which this receptor contributes to these behavioural processes have yet to be elucidated. In the present study, sustained application (5 min) of nicotine significantly lowered the threshold for synaptic plasticity, and thus a long-lasting potentiation was induced by a stimulus that would normally evoke only a short-term potentiation. This effect appeared to be mediated by alpha 7 nAChRs, as it was inhibited by the alpha 7 nAChR-specific antagonist alpha-bungarotoxin (100 nM), but not by mecamylamine (50 microM) or dihydro-beta-erythroidine (DH beta E; 1 microM) at concentrations known to be selective for non-alpha 7 nAChRs. Further pharmacological dissection revealed that the effect was also abolished by the NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 50 microM). This blockade, however, unmasked a slowly developing nicotine-induced potentiation of field excitatory postsynaptic potential that appeared to be dependent on both alpha 7 nAChR activation and non-alpha 7 nAChR desensitisation. This secondary effect of nicotine was blocked by a combination of picrotoxin (50 microM) and saclofen (100 microM), and thus appeared to be mediated via GABAergic interneurons. The important implication of this study was that the sustained application of alpha 7 nAChR agonists could modulate the conditions for synaptic plasticity through multiple transduction pathways, and not simply the inactivation of alpha 7 nAChRs. These alpha 7-nAChR-dependent mechanisms could reconcile the discrepancies between the previously reported behavioural versus electrophysiological effects of nicotine in the hippocampus. Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation Effects of sustained alpha 7 nAChR stimulation

2-Amino-5-phosphonovalerate↗
PubMed2005

Brain-derived neurotrophic factor and antidepressant activity.

Brain-derived neurotrophic factor (BDNF) is a member of the structurally and functionally homologous neurotrophin family. It is the most widely distributed trophic factor in the brain, and participates in neuronal growth, maintenance, and use-dependent plasticity mechanisms such as long-term potentiation and learning. There are several lines of evidence supporting a role for BDNF in the treatment of depression. This paper reviews the neurotrophin hypothesis of antidepressant action, and examines our current understanding of activity-dependent mechanisms of BDNF expression and function in limbic regions of the brain. Our discussion starts with the original observations of monoaminergic neurotransmitter dysfunction that served as the basis for early antidepressant drug development, and outlines evidence for neurodegeneration and functional deficits existing with chronic stress and depression. We continue with evidence that enhancement in neurotrophic support and associated augmentation in synaptic plasticity and function may form the basis for antidepressant efficacy, and serve as a current and future focus in the quest for more rapid-acting and effective medication treatments. Finally, we follow the current search for the intracellular mechanisms of antidepressant interventions that may bring the monoaminergic and neurotrophic hypotheses together, and help us to more fully understand the roles of both neurotransmitter and growth factor. Principal challenges to the neurotrophin hypothesis, and inconsistencies between clinical and preclinical research results, are also pointed out, as these also guide future experiments that will refine our understanding of treatment mechanisms.

Animals↗
PubMed1999

Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia.

Dysfunction of the dorsolateral prefrontal cortex appears to be a central feature of the pathophysiology of schizophrenia, and this dysfunction may be related to alterations in gamma aminobutyric acid (GABA) neurotransmission. Determining the causes and consequences of altered GABA neurotransmission in schizophrenia, and the relationship of these changes to other abnormalities in prefrontal cortical circuitry, requires an understanding of which of the multiple subpopulations of cortical GABA neurons are affected. The chandelier class of GABA neurons, especially those located in the middle layers of the prefrontal cortex (PFC), have been hypothesized to be preferentially involved in schizophrenia because they 1) receive direct synaptic input from dopamine axons, 2) exert powerful inhibitory control over the excitatory output of layer 3 pyramidal neurons, and 3) undergo substantial developmental changes during late adolescence, the typical age of onset of schizophrenia. Consistent with this hypothesis, the axon terminals of chandelier neurons, as revealed by immunoreactivity for the GABA membrane transporter, are reduced substantially in the middle layers of the PFC in schizophrenic subjects. This alteration appears to be selective for the chandelier class of GABA neurons and for the disease process of schizophrenia. These findings provide insight into the pathophysiologic mechanisms underlying prefrontal cortical dysfunction in schizophrenia, and they reveal new targets for therapeutic intervention in this illness.

Adolescent↗
PubMed1991

The effect of excessive weight reduction on peripheral and central nervous functions. A study in obese patients treated by gastric banding.

Twenty-four obese patients were studied before and 3, 6, and 12 months after gastric banding to see if the excessive weight reduction caused any dysfunction of the peripheral or central nervous system or both. Postoperatively the patients were assumed to be able to keep their intake to 800-1000 kcal/day together with a multivitamin supplement. Electromyography, electroneurography and vibratory thresholds were used to assess the peripheral, somatosensory and visual evoked potentials to assess the central nervous and synaptic functions. Regular clinical and neurological assessments were made as well as laboratory examinations including total potassium estimations to calculate lean body mass. The mean weight loss and the mean lean body mass reduction amounted to 20.5% and 18.4% at 3 months, and to 30.3% and 10.2% at 12 months, respectively. Electromyography showed signs of acute denervation in the anterior tibial muscle in one patient 3 and 6 months after operation, but restitution after 12 months despite continuous weight loss. In the left peroneal nerve the electroneurography showed a trend with slight successive reduction of the conduction velocity in the postoperative period. No abnormalities of the vibratory thresholds were found postoperatively. Somatosensory and visual evoked potentials were normal in all patients and no significant changes were observed during the postoperative period. The present study did not reveal any significant dysfunction of the peripheral or central nervous system as a result of excessive weight loss in obese adults undergoing weight reducing surgery.

Adult↗
PubMed1994

Comparative effects of inorganic divalent mercury, methylmercury and phenylmercury on membrane excitability and synaptic transmission of CA1 neurons in hippocampal slices of the rat.

Comparative effects of inorganic mercury (Hg2+), methylmercury (MeHg) and phenylmercuric acetate (PMA) on central synaptic transmission were examined by recording field potentials from CA1 neurons of rat hippocampal slices before and after acute bath application of mercurials at 20 and 100 microM. At 100 microM, Hg2+ decreased the amplitude of population spikes (PSs) to complete block; average time to block was 25 +/- 4 min. Application of 20 microM Hg2+ for 120 min gradually decreased PS amplitude to 33% of control. Effects of Hg2+ on excitatory postsynaptic potentials (EPSPs) were comparatively slow. Application of 100 microM Hg2+ for 120 min only reduced EPSP amplitude to 60% of control; no complete block occurred, suggesting an effect primarily on the postsynaptic CA1 cell membrane. In contrast to Hg2+, MeHg at 20 and 100 microM first increased amplitudes of PSs and EPSPs significantly and then decreased both to complete block. Average times to block of PSs and EPSPs by 100 microM MeHg were 41 +/- 4 and 42 +/- 4 min, respectively. PMA caused similar effects on PSs and EPSPs as did MeHg. However, unlike MeHg, the increased amplitudes of PSs and EPSPs by PMA were not statistically significant. At 20 microM, PMA appeared to be more effective at blocking PSs and EPSPs than were Hg2+ and MeHg. Washing slices with artificial cerebrospinal fluid containing 1 mM D-penicillamine completely reversed the effects of Hg2+ on PSs and EPSPs and effects of MeHg on EPSPs in 90 min, but only partially reversed the effects of MeHg on PSs. D-penicillamine could reverse neither the effects of PMA on PSs nor EPSPs. It is concluded that these perturbations produced damage to the associated physiological functions leading to CNS dysfunctions.

Animals↗