Management of orofacial pain.
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Brain Diseases↗
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Results for “synaptic dysfunction”
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Chronic developmental lead exposure and hippocampal long-term potentiation: biphasic dose-response relationship.
Developmental exposure to lead (Pb) has long been associated with reductions in intellectual function in children and behavioral impairments in animal models of learning and memory. We have used long-term potentiation (LTP) in the dentate gyrus of the Pb-exposed rats to determine the potential of a reduced capacity for synaptic plasticity to contribute to Pb-induced cognitive dysfunction. Previous work demonstrated that developmental exposure resulting in moderate blood concentrations of Pb increase the threshold for induction of long-term potentiation (LTP) in the dentate gyrus in vivo. These findings were also suggestive of reductions in LTP magnitude (Gilbert et al., 1996). The present study was designed to further examine the effects of Pb on LTP magnitude and to determine if lower blood Pb levels commonly encountered in children are also effective in impairing synaptic plasticity in this rodent model. Pregnant dams were exposed to control tap water or 0.1, 0.2, 0.5 or 1.0% Pb-acetate in the drinking water beginning just prior to parturition (gestational day 16, GD16). Male offspring were weaned at 21 days of age (PN21) to the same solution given their dams and continued on this regimen until testing. As adults, animals were anesthetized with urethane and stimulating and recording electrodes placed in the perforant path and dentate gyrus, respectively. Post-train I/O functions taken 1 hour after delivery of a series of six high frequency (400Hz) trains revealed a reduced capacity for LTP of the PS amplitude and EPSP slope in Pb-exposed animals in all but the 1.0% group, indicative of a biphasic dose-effect relationship. The 1.0% Pb exposure was clearly less effective than the lower exposure levels in reducing LTP magnitude, and did not differ significantly from control values. The mechanisms underlying the reduced efficacy of higher exposure levels of Pb to impair LTP are not clear. Blood (26-117 microg/dl) and brain (220-1812 ng/g tissue) concentrations of Pb were elevated as a function of increasing exposure (0.1%-1.0%) and cannot readily account for the lack of an effect in the 1.0% group on LTP. We have observed a similar profile in hippocampal glutamate release employing a similar range of exposure levels, i.e., reduction of glutamate release that is absent at higher concentrations of Pb in the drinking water (Lasley et al., 1998). These and previously reported data suggest that the ability of Pb to diminish presynaptic transmitter release contributes to a reduced capacity for LTP at lower exposure levels. The reversal of the effect of Pb on glutamate release that accompanies higher exposure levels may serve to compensate for the mechanism underlying the LTP impairment and form the basis for the biphasic dose-response pattern seen with chronic developmental exposure.
Animals↗
The neurobiology of learning and memory: elucidation of the mechanisms of cognitive dysfunction.
This paper reviews evidence which suggests that there is a series of events at the synaptic level, beginning with synaptic activation, responsible for the formation of memories. Synaptic use above routine levels activates NMDA receptors which allows calcium influx into the neuron. Calcium appears to trigger changes in synapse and synaptic terminal shape (via cytoskeletal activation), and an increase in synaptic size (via new protein synthesis). New synapses ultimately form either de novo or by splitting, and new dendritic spines and dendritic length is added. Several forms of cognitive dysfunction, such as Downs syndrome, aging and Alzheimer's disease, and exposure to the neurotoxins lead or aluminum appear to involve, at least in part, disruptions in this process. Evidence is reviewed to support the theory that memories may involve alterations in specific sets of synapses located at specific dendritic locations; this theory may explain some of the learning and memory deficits seen in conditions resulting in cognitive dysfunction.
Cognition Disorders↗
Carbonic anhydrase gating of attention: memory therapy and enhancement.
Enhancement of memory acquisition and recall represents an important pharmacological goal in the treatment of cognitive disorders. In addition to its involvement in pH regulation, HCO3- reabsorption and CO2 expiration, carbonic anhydrase plays a crucial role in signal processing, long-term synaptic transformation and attentional gating of memory storage. Carbonic anhydrase dysfunction impairs cognition and is associated with mental retardation, Alzheimer's disease and aging. The pharmacological profile of carbonic anhydrase has been refined and specific activators have been developed. In this article, an integrated view of the involvement of carbonic anhydrase activity in synaptic plasticity and cognition will be presented, with particular focus on attentional gating of spatial learning and memory.
Alzheimer Disease↗
Substance P given intrathecally at the spinal T9 level increases adrenal output of adrenaline and noradrenaline in the rat.
Administration of 10 micrograms of substance P intrathecally to the spinal T9 level of the adult rat, anaesthetized with urethane, provoked an increase in free catecholamines in plasma taken from the inferior vena cava. Adrenaline levels at 1 min after administration were 154.8 +/- 10.8% (mean +/- SE; n = 11) of preadministration levels and noradrenaline levels were 153.5 +/- 11.8% of preadministration levels. Differences between the values of free catecholamines in animals given substance P vs those given vehicle only were statistically significant at 1 and 10 min postinjection, but not at 30 min. Administration of a substance P analogue with central antagonistic properties 15 min before substance P was given prevented expression of the effects of substance P. These results suggest that substance P may be an excitatory chemical mediator of synaptic transmission in spinal pathways controlling adrenal medullary output. Thus dysfunction of substance P mechanisms may underlie some animal models of hypertension and may be involved in some cases of essential hypertension in man as well as in autonomic dysfunction associated with some neurological entities.
Adrenal Medulla↗
A light and electron microscopic study of oedematous human cerebral cortex in two patients with post-traumatic seizures.
PRIMARY OBJECTIVE: Brain cortical biopsies of two patients with clinical diagnosis of complicated brain trauma who had seizures, were studied by means of light and electron microscopes in order to correlate structural alterations with seizure activity. METHODS AND PROCEDURES: Biopsy samples of left frontal cortex and right parietal cortex were processed by current techniques for light and transmission electron microscopy. RESULTS: The tissue showed severe vasogenic oedema with perivascular and intraparenchymatous haemorrhages. At the capillary wall, increased vesicular and vacuolar transendothelial transport, open endothelial junctions, thickened basement membrane and swollen perivascular astrocytic end-feet were observed. Some pyramidal and non-pyramidal nerve cells appeared dense and shrunken and others exhibited marked intraneuronal enlargement of membrane compartment. The myelinated axons displayed signs of degeneration and a process of axonal sprouting. Numerous swollen asymmetrical axo-dendritic synaptic contacts were observed in the neuropil, which exhibited mostly closely aggregated spheroidal synaptic vesicles toward the presynaptic membrane and numerous exocytotic vesicles sites. The perisynaptic astrocytic ensheathment appeared retracted or absent, whereas the extracellular space appeared notably dilated. Synaptic disassembly was also observed. CONCLUSION: The findings demonstrate, in two patients with post-traumatic seizure activity, brain barrier dysfunction, vasogenic oedema, anoxic-ischaemic neurons, axonal sprouting, numerous altered excitatory synapses and synaptic disassembly. Some considerations on clinical and research applications are discussed.
Adolescent↗
Diphenylhydantoin protects against hypoxia-induced impairment of hippocampal synaptic transmission.
The ability of diphenylhydantoin (DPH) to protect against hypoxia-induced neuronal damage was examined using electrophysiological recordings of extracellular evoked potentials from CA1 pyramidal neurons of rat hippocampal slices in vitro. In normal medium, a 15-min hypoxic insult (95% N2/5% CO2) produced rapid and complete loss of Schaffer collateral synaptic transmission, which only recovered to 20% of pre-hypoxia values after 90 min of reoxygenation. DPH (20 microM) bath applied prior to onset of hypoxia slowed the loss of transmission during hypoxia, and led to 75% recovery of evoked potentials upon reoxygenation. Thus, DPH appears to protect against hypoxia-induced loss of synaptic transmission, and may thereby lessen neuronal damage and cognitive dysfunction associated with stroke.
Animals↗
Identification of amyloid precursor protein in synaptic plasma membrane.
Although the etiology of Alzheimer's disease has not been elucidated yet, dysfunction and loss of synapses are believed to cause dementia. Recent studies suggest that the primary cause of the disease is closely related to the aberrant processing of the amyloid precursor protein (APP). To investigate the localization of APP at synaptic sites, we obtained synaptic plasma membrane and synaptic vesicles from rat brain. Enhanced chemiluminescence (ECL) western blot analysis using two specific polyclonal antibodies against APP revealed strong APP immunoreactivity in the synaptic plasma membrane, but not in the synaptic vesicle fraction. These data indicate that APP is localized at the synaptic plasma membrane and may play a role in physiological synaptic activity. Alternative localization or aberrant processing of APP at the synaptic site may cause impairment of synaptic function in Alzheimer's disease.
Amyloid beta-Protein Precursor↗
Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats.
Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24 mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were tested in a spatial version of the Morris water maze. After 16 weeks of diabetes, in the same groups, blood flow in the hippocampus and thalamus was measured by hydrogen clearance microelectrode polarography. In a separate study, hippocampal long-term potentiation was measured after 26 weeks of diabetes. Water maze performance and hippocampal long-term potentiation were impaired in diabetic rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic controls. Enalapril treatment significantly improved water maze performance (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats.
Angiotensin-Converting Enzyme Inhibitors↗
[Nootropic drugs and their action mechanisms in relation to the neuropathobiology of senile dementia. I. Neurotransmission disorders in the brain].
The author presents a review of agents which are presently included in the category of nootropic drugs and comments the relations between the pharmaceutical research of new nootropic and progressing knowledge of the neuropathobiology of Alzheimer's disease, senile dementia and degenerative processes of aging brain in general. In Part I., several hypotheses are discussed which explain the biological substrate of senile cognitive decline by disturbed brain synaptic neurotransmission (cholinergic, monoaminergic, petidergic) and, at the same time, drugs are suggested which may exert regulatory action on these dysfunctions.
Alzheimer Disease↗
Convergence of hippocampal and dopaminergic input onto identified neurons in the nucleus accumbens of the rat.
The hippocampal input to the nucleus accumbens was interrupted by an electrolytic lesion of the fimbria-fornix. Boutons degenerating as a result of this lesion were found in asymmetric synaptic contact with dendritic spines and shafts in the medial part of the nucleus accumbens. Dopaminergic fibres and terminals in this area, identified using an antibody to tyrosine hydroxylase, established symmetrical synaptic contacts with dendritic shafts, spines and somata. In material where neurons in the nucleus accumbens had been Golgi-impregnated, it was found that the hippocampal and dopaminergic inputs converge onto the same neurons, and that the post-synaptic targets could be either spiny or aspiny neurons. It has been suggested that hippocampal dysfunction is involved in schizophrenia and this convergence of input from the hippocampus onto the same neurons that are post-synaptic to the dopaminergic input, which presumably originates from neurons in the ventral tegmental area, may provide an anatomical basis for the therapeutic effects of neuroleptic drugs which are dopamine antagonists.
Animals↗
Alpha-1 adrenoceptor hyperresponsiveness in three neuropathic pain states: complex regional pain syndrome 1, diabetic peripheral neuropathic pain and central pain states following spinal cord injury.
The pathophysiology of the pain associated with complex regional pain syndrome, spinal cord injury and diabetic peripheral neuropathy is not known. The pain of complex regional pain syndrome has often been attributed to abnormal sympathetic nervous system activity based on the presence of vasomotor instability and a frequently reported positive response, albeit a temporary response, to sympathetic blockade. In contrast, the pain below the level of spinal cord injury and diabetic peripheral neuropathy are generally seen as deafferentation phenomena. Each of these pain states has been associated with abnormal sympathetic nervous system function and increased peripheral alpha-1 adrenoceptor activity. This increased responsiveness may be a consequence of alpha-1 adrenoceptor postsynaptic hypersensitivity, or alpha-2 adrenoceptor presynaptic dysfunction with diminished noradrenaline reuptake, increased concentrations of noradrenaline in the synaptic cleft and increased stimulation of otherwise normal alpha-1 adrenoceptors. Plausible mechanisms based on animal research by which alpha-1 adrenoceptor hyperresponsiveness can lead to chronic neuropathic-like pain have been reported. This raises the intriguing possibility that sympathetic nervous system dysfunction may be an important factor in the generation of pain in many neuropathic pain states. Although results to date have been mixed, there may be a greater role for new drugs which target peripheral alpha-2 adrenoceptors (agonists) or alpha-1 adrenoceptors (antagonists).
Animals↗
Effects of methylmalonic and propionic acids on glutamate uptake by synaptosomes and synaptic vesicles and on glutamate release by synaptosomes from cerebral cortex of rats.
Neurological dysfunction is common in patients with methylmalonic and propionic acidemias. However, the mechanisms underlying the neuropathology of these disorders are far from understood. In the present study we investigated the in vitro effects of methylmalonic (MMA) and propionic (PA) acids at various concentrations (1 microM-5 mM) on three parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[3H]glutamate by synaptosomes, Na+-dependent L-[3H]glutamate uptake by synaptosomes and Na+-independent L-[3H]glutamate uptake by synaptic vesicles from cerebral cortex of male adult Wistar rats. The results showed that MMA significantly increased potassium-induced but not basal L-[3H]glutamate release from synaptosomes with no alteration in synaptosomal L-[3H]glutamate uptake. A significant reduction of L-[3H]glutamate incorporation into vesicles caused by MMA was also detected. In contrast, PA had no effect on these parameters. These findings indicate that MMA alters the glutamatergic system. Although additional studies are necessary to evaluate the importance of these observations for the neuropathology of methylmalonic acidemia, it is possible that the effects elicited by MMA may lead to excessive glutamate concentrations at the synaptic cleft, a fact that may explain previous in vivo and in vitro findings associating MMA with excitotoxicity.
Animals↗
[Pathophysiological characterization of congenital myasthenic syndromes: the example of mutations in the MUSK gene].
Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and are characterized by a dysfunction of the neurotransmission. They are heterogeneous at their pathophysiological level and can be classified in three categories according to their presynaptic, synaptic and postsynaptic origins. We report here the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth. These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.
Animals↗
Sexual functioning in depressed outpatients taking mirtazapine.
OBJECTIVES: One-third of patients with untreated depression have sexual difficulties manifested by decreased libido, erectile dysfunction or delayed ejaculation. This dysfunction may be exacerbated by stimulation of post-synaptic serotonin 5HT2 receptors, a side-effect of most widely-used antidepressant medications, especially the selective serotonin reuptake inhibitors (SSRIs). Mirtazapine is an atypical antidepressant with alpha 2 adrenergic antagonist and serotonin 5-HT2 and 5-HT3 receptor-blocking activity. In theory, it should not worsen and perhaps may improve sexual function. This pilot study investigated sexual functioning and antidepressant activity in depressed patients taking mirtazapine. EXPERIMENTAL DESIGN: Twenty-five (F = 18, M = 7) sexually active adult outpatients with a DSM-IV-diagnosis of major depressive episode entered a 12-week, flexible-dosing, open-label pilot study. The Arizona Sexual Experiences Scale (ASEX) assessed sexual functioning and the Hamilton Depression Rating Scale (HAM-D) assessed depressive symptoms on a bimonthly basis. PRINCIPAL OBSERVATIONS: Desire, arousal/lubrication, and ease/satisfaction of orgasm improved (by 41%, 52%, and 48%, respectively) in the depressed women. In men, desire, arousal/erection, and ease/satisfaction of orgasm also improved (by 10%, 23% and 14%, respectively) but much more modestly. HAM-D, Clinical Global Impression (CGI) Sheehan Disability Scale (SDS), and Symptom Checklist-90 (SCL-90) scores improved in both groups. There was a 50% dropout rate among women before six weeks of treatment. However, the ASEX and HAM-D scores of the groups terminating before and after six weeks of treatment showed similar rates of improvement. CONCLUSIONS: Mirtazapine has a beneficial effect on sexual functioning in both depressed women and men. Longer-term double-blind research assessing sexual function during the administration of mirtazapine as well as other antidepressants is recommended.
Adult↗
Reduced reactivity to novelty, impaired social behavior, and enhanced basal synaptic excitatory activity in perforant path projections to the dentate gyrus in young adult mice deficient in the neural cell adhesion molecule CHL1.
The neural cell adhesion molecule CHL1 is implicated in neural development in the mouse and has been related to psychiatric disorders in humans. Here we report that mice constitutively deficient for CHL1 display reduced reactivity to environmental stimuli and reduced expression of social behaviors, whereas cognitive, motor and olfactory functions are normal. Basal synaptic transmission and plasticity in seven major excitatory connections in the hippocampus were analyzed to test whether dysfunctions in this brain region, which controls complex behaviors, correlate with the behavioral alterations of CHL1 deficient mice. We found that basal synaptic transmission in lateral and medial perforant path projections to the dentate gyrus is elevated in CHL1-deficient mice. Taking in consideration the function of these synapses in processing information from cortical areas, we hypothesize that constitutive ablation of CHL1 leads to reduced capability to react to external stimuli due to dysfunctions in the dentate gyrus.
Animals↗
Identification of normal and pathological aging in prospectively studied nondemented elderly humans.
Results of a standardized histochemical and immunocytochemical analysis of the brains of 14 nondemented elderly humans for whom prospective neurological and neuropsychological data had been collected for 3 to 8 years before death suggested that nondemented elderly humans fall into two pathological subgroups that are not clinically distinguishable. One was associated with moderate to marked cerebral amyloid deposition ("pathological aging"), while the other had either minimal or no amyloid deposition ("normal aging"). Neocortical and hippocampal neurofibrillary degeneration was either completely absent or of very limited degree in both subgroups. Both subgroups had ubiquitin-immunoreactive dystrophic neurites in the cerebral cortex and granular degeneration of myelin in white matter. These ubiquitin-immunoreactive structures seem to be a universal and invariant manifestation of brain aging, but the same cannot be said for amyloid deposition and neurofibrillary degeneration. Pathological aging might be preclinical Alzheimer's disease, but it currently cannot be distinguished from normal aging by even sensitive neuropsychological measures. These findings provide strong support for the hypothesis that cerebral amyloid deposition is not necessarily associated with clinically apparent cognitive dysfunction and that additional factors, such as neuronal or synaptic loss or widespread cytoskeletal aberrations, are necessary for dementia in AD.
Aged↗
Molecular pathways to neurodegeneration.
The molecular bases underlying the pathogenesis of neurodegenerative diseases are gradually being disclosed. One problem that investigators face is distinguishing primary from secondary events. Rare, inherited mutations causing familial forms of these disorders have provided important insights into the molecular networks implicated in disease pathogenesis. Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, excitotoxic insult, oxidative and nitrosative stress, mitochondrial injury, synaptic failure, altered metal homeostasis and failure of axonal and dendritic transport represent unifying events in many slowly progressive neurodegenerative disorders.
Alzheimer Disease↗