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PubMed1996

Neuronal and glial localization of two GABA transporters (GAT1 and GAT3) in the rat cerebellum.

The localization of GABA transporters (GAT1 and GAT3) was examined immunocytochemically in the rat cerebellum at both light and electron microscopic levels using antibodies specific for each subtype. Immunoblot analysis showed that the antibodies against GAT1 and GAT3 specifically recognized their respective antigens in the cerebellum. Both GAT1 and GAT3 were found in the neuropil but not in neuronal somata or glial cell bodies. GAT1 immunoreactivity was seen throughout all layers of the cerebellar cortex with the highest immunoreactivity in the molecular layer, but little immunoreactivity was found in the deep cerebellar nuclei. GAT1 immunoreactivity was seen in the pinceau area of the Purkinje cell layer and in the mossy fiber glomeruli in addition to the neuropil of the molecular layer. Weak GAT3 immunoreactivity was found in the granular layer of the cerebellar cortex, and intense immunoreactivity was observed around the unstained large neurons in the deep cerebellar nuclei. Electron microscopic analysis of the cerebellum revealed that GAT1 immunoreactivity was predominantly localized in the presynaptic terminals, while GAT3 immunoreactivity was localized in the glial processes. These results suggested that GABAergic transmission at synapses is terminated by three GABA uptake systems, (1) only neuronal uptake through GAT1, (2) only glial uptake through GAT3, and (3) both neuronal and glial uptake through GAT1 and GAT3 respectively, and also that the GABA uptake system is different in each type of GABAergic neuron.

Animals↗
PubMed1994

Effect of hypothalamic 5,7-dihydroxytryptamine lesion on the anterograde transport of serotonin as measured with labeled alpha-methyl serotonin.

The anterograde axonal transport of serotonin along the medial forebrain bundle (MFB) 5 days after unilateral dorsal hypothalamic 5,7-dihydroxytryptamine (5,7-DHT) lesion was examined in rat brain. Measurements were done using in vivo synthesized radioactively labeled alpha-methyl serotonin (used here as a serotonin tracer), from i.v. injected labeled alpha-methyl-L-tryptophan, a substitute neurotransmitter and analog of serotonin. Data indicated that after destruction of the presynaptic terminals with 5,7-DHT, the rate of axonal transport of serotonin and/or the rate of serotonin synthesis in the spared and/or damaged neurons was increased. The rate of serotonin anterograde transport on the lesioned side was above 25 mm/d compared to 12.31 +/- 0.49 mm/d on the contralateral side and 12.13 +/- 0.44 mm/d in control (sham injected) rats. The difference in rate between the lesioned and control rats was highly significant; P < 0.005 (two-tailed t-test). The amount of neurotransmitter anterogradely transported along the medial forebrain bundle and/or synthesized in the neurons was 18.8 +/- 4.1 times greater on the side of the 5,7-DHT hypothalamic lesion than that on the contralateral sides or that found in the saline-injected rats. There was no difference in the radioactivity found on the left or right side of the medial forebrain bundle in the rats 5 days after lesion in the rostal midbrain with 5,7-DHT. Five days after the lesion there was also no difference in the anterograde protein transport measured by stereotaxic injection of [3H]proline into the dorsal raphe.

5,7-Dihydroxytryptamine↗
PubMed1994

Presynaptic modulation by dopamine and GABA opens a potassium channel in rat cortical, striatal and hippocampal synaptosomes via eicosanoids.

Using a K(+)-sensitive electrode in synaptosomal preparations, the presynaptic modulating effect of dopamine and GABA in opening a K+ channel was investigated. In cortical, striatal and hippocampal synaptosomes dopamine D1 and D2 agonists and a GABAB agonist promoted the efflux of K+ in all three preparations. The effect was blocked by the cyclooxygenase inhibitor, indomethacin suggesting that eicosanoids act as second messengers in these systems. The inference in these studies is that dopamine and GABA hyperpolarize presynaptic terminals thereby reducing Ca2+ influx and thus inhibiting the evoked release of transmitters.

Animals↗
PubMed1996

GABA transporter heterogeneity: pharmacology and cellular localization.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. GABA is cleared from the synaptic cleft by specific, high-affinity, sodium- and chloride-dependent transporters, which are thought to be located on presynaptic terminals and surrounding glial cells. While early studies suggested a distinction between neuronal and glial GABA transport, molecular cloning has revealed the existence of genes for four distinct GABA transporters (termed GAT-1, GAT-2, GAT-3 and BGT-1), thus revealing a greater heterogeneity than previously suspected. Heterologous expression has allowed a detailed characterization of their pharmacological properties, and has revealed that GAT-1 is the site of action of the anticonvulsant drug, Tiagabine. In-situ hybridization and immunocytochemistry demonstrate that each transporter has a unique regional distribution in the brain; in conjunction with experiments utilizing cell cultures, the neuronal vs glial localization of the various transporters is being elucidated. Future studies will be directed at determining the role of each transporter in the regulation of GABAergic transmission, and in the design of additional subtype-specific inhibitors, which may serve as novel therapeutic agents for the treatment of neuropsychiatric disorders.

Animals↗
PubMed1982

Synaptic remodelling and astrocytic hypertrophy in rat cerebral cortex from early to late adulthood.

Ultrastructural observation of the molecular layer of the parietal cortex of rats, aged 3, 6, 10 and 17 months, revealed various atypical synaptic profiles besides typical synapses. The atypical synapses were frequently in the vicinity of hypertrophied astrocytic profiles, and were sometimes completely surrounded by astrocytic processes. The presynaptic terminal contained either no vesicles or a few small distorted vesicles. Vacant postsynaptic terminals were occasionally seen. The total surface area of astrocytic profiles and the numbers of atypical synapses increased significantly between 3 and 10 months. The astrocytic acquisition of degenerating terminals was repeatedly observed over this period. Since there was no decrease in total synaptic number at this age, the astrocytic phenomenon may represent a stage in a continuous cycle of synaptic loss and replacement in the normal brain. By 17 months, when total synapse numbers decrease, synaptic replacement may be less than optimal.

Aging↗
PubMed1983

Ultrastructural studies on synaptic formations in dissociated fetal mouse brain cultures.

Sequential electron microscopic studies of cultures of neurons derived from dissociated fetal mouse brain on the eleventh day of gestation revealed the formation of well-developed synapses during the second and third weeks of growth in vitro. Synaptic junctions were associated with synaptic vesicles nd dense synaptic membranes. Dense-core vesicles were also observed frequently in presynaptic terminals.

Animals↗
PubMed1989

Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease.

Alzheimer disease (AD) as well as other dementing disorders are characterized by a continuous loss of neurons in cortical and subcortical areas and probably by an extensive synaptic loss. In order to substantiate and localize the loss of synapses in AD, we quantified by microdensitometry the neuropil immunoreactivity to an antibody that labels the protein synaptophysin (p38), which is localized in the presynaptic terminals. We found in the AD cases an average 50% decrease in the density of the granular neuropil immunoreaction in parietal, temporal and midfrontal cortex. In contrast, Pick disease cases presented close to normal values in parietal cortex, but major losses in temporal and frontal cortex. Our data strongly suggest an important role of synapse loss in dementia.

Aged↗
PubMed1990

GABAB agonists modulate a transient potassium current in cultured mammalian hippocampal neurons.

Depolarization of voltage-clamped cultured rat hippocampal neurons from holding potentials more negative than -60 mV produced a transient outward current with the characteristics of an A-current: it was 50% inactivated at a holding potential of -85 mV and blocked by 4-aminopyridine (1 mM). In the presence of GABA or baclofen (50-200 microM), with or without bicuculline, inactivation of this current was shifted to more positive potentials so that there was little inactivation at -70 mV. Activation of the A-current was also shifted to more positive potentials by these agonists, but the voltage dependence of activation of the sodium current was unaffected. If A-currents with similar properties can influence the time course of action potentials in presynaptic terminals. GABAB agonists could make action potentials briefer by potentiating the A-current and hence depress transmitter release.

4-Aminopyridine↗
PubMed1991

Interaction of Ca-channel blockers and high pressure at the crustacean neuromuscular junction.

Exposure to high pressure causes a significant depression of synaptic transmission. We examined the effects of various Ca-channel blockers and their interaction with high pressure on excitatory neuromuscular junction currents (EJCs) of lobster abdominal muscles. Reduced [Ca2+]o to half of normal concentration or exposure to 40-60 microM CdCl2, 10-20 microM NiCl2 and 1 microM omega-conotoxin decreased EJCs by 50%. Nifedipine, Nitrendipine and Bay K-8644 were ineffective. Either Ca-blockers or reduced [Ca2+]o, enhanced EJC suppression exerted by high pressure. The data suggest that high pressure primarily affects Ca2+ inflow at the presynaptic terminals through N-type voltage-gated Ca-channel.

Animals↗
PubMed1991

The spatial pattern of the synaptic vesicular apparatus as a correlate of transmitter storage models.

A statistical stereological approach which allows one to derive a three-dimensional pattern of synaptic vesicle accumulation in relation to the active zone from an analysis of electron micrograms (random sections) of synapses is described. This approach is illustrated with a study of presynaptic terminals from the dorsal horn of the cat spinal cord, based on the morphometrical treatment of 105 micrographs containing 5190 synaptic vesicles. The spatial pattern obtained was found to have a bimodal shape, which can be considered a possible structural correlate of the two-pool model of transmitter storage. The connection of similar quantitative estimates with physiological data is discussed.

Animals↗
PubMed1991

Abnormal brain spectrin immunoreactivity in sprouting neurons in Alzheimer disease.

Brain spectrin is a major membrane skeleton protein that participates in cellular transport, cell morphogenesis, neurotransmitter release and growth cone adhesion. The present study showed that in Alzheimer disease (AD) neuropil, brain spectrin immunoreactivity is co-localized with synaptophysin in the presynaptic boutons. At the ultrastructural level, brain spectrin immunoreactivity was observed in the presynaptic terminals and in the axoplasm of some myelinated and unmyelinated fibers. In addition to this normal localization of brain spectrin in the AD brain, we also found brain spectrin immunoreactivity associated with abnormal patchy lesions in the AD neuropil. Confocal laser imaging and immunoelectron microscopy revealed that these lesions corresponded to thick cellular processes derived from neurons. The findings that these structures were anti-neurofilament positive but anti-glial fibrillary acidic protein (GFAP) and Ricinus communis agglutinin I (RCA-I) negative confirm their neuronal origin, and rule out the possibility of glial origin. These structures could represent either atypical axonal or dendritic processes derived from sprouting neurons or the accumulation of brain spectrin degradation products in degenerating neurons.

Aged↗
PubMed1991

Relationship between non-fibrillary amyloid precursors and cell processes in the cortical neuropil of Alzheimer patients.

We examined the ultrastructural localization of amyloid beta-protein in 8 Alzheimer neocortical biopsies. Intense immunoreactivity was located extracellularly on amyloid fibrils and amorphous material. Amorphous labelled material was also found in cell processes. No ultrastructural cell marker, such as glial fibrils, glycogen, tubules, paired helical filaments (PFHs) or synaptic vesicles could be seen in these processes that could allow their identification as glial processes, neurites or presynaptic terminals, respectively; occasional membrane stacks were observed. These findings suggest that preamyloid deposits are related to cell processes and, by elimination, that postsynaptic terminals may be involved in abnormal metabolism of the amyloid fibril precursors.

Aged↗
PubMed1992

Monensin can transport calcium across cell membranes in a sodium independent fashion in the crayfish Procambarus clarkii.

Monensin, a Na(+)-selective ionophore, enhances transmitter release when applied to crustacean and frog neuromuscular junctions. Monensin is believed to raise intracellular sodium ([Na+]i) which in turn elevates intracellular calcium ([Ca2+]i). Using the fluorescent indicator fura-2, we measured [Ca2+]i in crayfish Procambarus clarkii presynaptic terminals during monensin application in normal Ringer, zero-calcium Ringer and zero-sodium Ringer to determine if [Ca2+]i increases with monensin application and if so by what mechanism. In normal Ringer, monensin, 10 microM and 100 microM, elevated [Ca2+]i by 440 nM and 7 microM respectively. This rise in [Ca2+]i was dependent on external calcium, as [Ca2+]i did not increase in zero-calcium Ringer. However, in a zero-sodium Ringer, monensin (10 microM) elevated [Ca2+]i by 370 nM. It is important to recognize that monensin, thought to be a sodium-selective ionophore, can transport calcium across the cytoplasmic membrane in a sodium-independent manner.

Animals↗
PubMed1994

Phosphoinositide kinase activities in synaptosomes prepared from brains of patients with Alzheimer's disease and controls.

Previously, phosphatidylinositol (PI) kinase activity in cytosolic fractions prepared from postmortem tissue of the cerebral cortex from patients with Alzheimer's disease (AD) appeared to be lower than that of age-matched controls [Jolles et al., J. Neurochem., 58 (1992) 2326-2329]. In the study presented here, PI and PIP (phosphatidylinositol phosphate) kinase activities were studied in synaptosomes prepared from postmortem brain tissue of AD patients and age-matched controls. Firstly, PI kinase activity in synaptosomes prepared from the frontal superior gyrus of AD brain was 30% lower than in synaptosomes prepared from postmortem tissue of control brain. PIP kinase activity was the same in AD and control synaptosomes. Secondly, the yield of synaptosomal protein (micrograms protein per mg tissue wet weight) was lower in preparations from AD brain than in preparations from control brain, which could be a manifestation of a loss of presynaptic terminals in the frontal cortex. These results suggest that the difference in PI kinase activity between AD and control brain tissue may originate from differences in intact neurons in view of the fact that synaptosomes can originate only from intact neurons.

1-Phosphatidylinositol 4-Kinase↗
PubMed1994

Synaptic and neuritic alterations during the progression of Alzheimer's disease.

Extensive synaptic and neuritic alterations in the neocortex and limbic system are characteristically found in Alzheimer's disease (AD). However, it is not known how early in the development of the disease these alterations occur. For the present study, we compared the synaptic and neuritic alterations among cases classified clinically and neuropathologically as early, mild and advanced AD. In early AD there was a 20% loss of synaptophysin-immunoreactive presynaptic terminals in the outer molecular layer of the hippocampal dentate gyrus (but not in the neocortex and entorhinal cortex), accompanied by increased amyloid precursor protein (APP) and Alz50 immunoreactivity in hippocampal and entorhinal cortex pyramidal neurons. These results suggest that abnormal neuronal expression of APP and cytoskeletal proteins in early stages might be involved in the mechanisms of synaptic pathology in AD.

Aged↗
PubMed1995

Extracellular phosphorylation of membrane protein modifies theta burst-induced long-term potentiation in CA1 neurons of guinea-pig hippocampal slices.

The involvement of ecto-protein kinase activity in activity-dependent long-term potentiation (LTP) was studied in CA1 neurons of guinea-pig hippocampal slices. Application of 5 microM K-252b, an ecto-protein kinase inhibitor, blocked LTP induced by a theta-burst stimulation (3 bursts composed of 5 pulses at 100 Hz with inter-burst intervals of 200 ms). On the other hand, under 10 microM RK682, an ecto-phosphatase inhibitor, a robust LTP was induced by a weak theta-burst stimulation (3 bursts composed of 3 pulses) which was just at the threshold for the induction of LTP in the control perfusate. These findings suggest that ATP released from presynaptic terminals during the burst stimulation plays an important role in the induction of LTP through phosphorylation of extracellular domains of synaptic membrane proteins, as the substrate for ecto-protein kinase.

Animals↗
PubMed1995

Changes in mobility of synaptic vesicles with assembly and disassembly of actin network.

In a presynaptic terminal, neurotransmitters are stored in synaptic vesicles and secreted into the synaptic cleft as a final step of cell signal transduction. At a static state, the vesicles are retained in the highly dense actin network. Prior to exocytosis, the dense actin network must disassemble or largely be organized. Actin networks are formed in vitro which retain synaptic vesicles prepared from rat cerebral cortex. Dynamic behaviors of synaptic vesicles are measured by the dynamic light scattering method. The D(app) values of synaptic vesicles confined in actin network became less than 1/4 those of free vesicles. The motions of synaptic vesicles are substantially restricted. This means that synaptic vesicles which are liberated from the actin network by detachment of synapsin 1 molecules are still trapped in the cage-like space of actin filaments. The actin network is disassembled by the actin severing protein, gelsolin, which is activated in the presence of microM level free Ca2+ ions. The D(app)(v) values of synaptic vesicles after severing the actin network return to those of free vesicles in the presence of short actin fragments. A molecular model for exocytosis in the synaptic terminal is constructed on the basis of these results.

Actin Cytoskeleton↗
PubMed1984

On the mechanism of central stimulation action of fencamfamine.

The stereotypy induced by fencamfamine (10 mg/kg i.p.) was compared in different groups of rats which had been pretreated with catecholaminergic drugs. Pretreatment with alpha-methyl-p-tyrosine (alpha-MpT) did not abolish the stereotypy, however the combination of alpha-MpT plus reserpine decreased, while reserpine alone increased this response. Pretreatment with haloperidol or metoclopramide reduced the intensity of stereotyped behaviour induced by fencamfamine, while phenoxybenzamine increased this behaviour. Fencamfamine showed low affinity for binding sites of [3H]haloperidol and [3H]dihydroergocriptine. These results support the view that fencamfamine is an indirectly acting drug of the non-amphetamine class, which releases both norepinephrine (NE) and dopamine (DA) from presynaptic terminals leading to stereotyped behaviour.

Animals↗