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PubMed1993

Glutamate uptake from the synaptic cleft does not shape the decay of the non-NMDA component of the synaptic current.

To study the role of glutamate uptake at central glutamatergic synapses, we used the uptake blocker L-transpyrrolidine-2,4-dicarboxylate (PDC). The effects of PDC on the glutamate uptake current in salamander retinal glia indicated that PDC competes with glutamate for transport on the uptake carrier and that 300 microM PDC should significantly reduce the uptake of glutamate during the synaptic current. In isolated rat hippocampal neurons, 300 microM PDC did not affect non-N-methyl-D-aspartate (NMDA) receptor currents, but reduced NMDA receptor currents by 30%. In hippocampal and cerebellar slices, whereas 300 microM PDC reduced the NMDA component of excitatory synaptic currents by 50%, it reduced the non-NMDA component only slightly with no change in its decay time constant. Thus, the decay rate of the non-NMDA component is not set by the rate of glutamate uptake from the synaptic cleft into the presynaptic terminal.

Animals↗
PubMed1994

Multivesicular release from excitatory synapses of cultured hippocampal neurons.

Release of neurotransmitter from presynaptic terminals occurs by exocytosis of vesicular contents into the synaptic cleft. We find that more than one quantum of transmitter can interact with the same population of postsynaptic NMDA receptors in conditions which increase the probability of transmitter release. Increasing release probability also results in proportional increases in both AMPA and NMDA receptor components of the synaptic current. These results suggest that the fraction of AMPA and NMDA receptors occupied by transmitter following the release of a single quantum is similar. Based on AMPA and NMDA receptor responses of outside-out patches to short applications of glutamate, we suggest that both receptor types may be saturated normally by synaptic release.

2-Amino-5-phosphonovalerate↗
PubMed1994

The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation.

We have addressed the role of Ca2+ channels in mossy fiber synaptic transmission and long-term potentiation (LTP). Whereas the induction of mossy fiber LTP is entirely normal when synaptic transmission is blocked by the glutamate receptor antagonist kynurenate, LTP is blocked in the absence of extracellular Ca2+. These findings suggest that presynaptic Ca2+ entry is essential for mossy fiber LTP. Therefore, the role of different types of presynaptic Ca2+ channels in synaptic transmission and LTP was investigated. Mossy fiber responses were little affected by the L-type Ca2+ channel blocker nifedipine. They were blocked partially by omega-conotoxin-GVIA (N-type) and almost entirely by omega-agatoxin-IVA (P-type). None of these antagonists blocked mossy fiber LTP, nor was its expression associated with a change in sensitivity of synaptic transmission to either of the two toxins. These results, together with previous findings, suggest that the induction of mossy fiber LTP is critically dependent on the entry of Ca2+ into the presynaptic terminal to trigger a series of steps resulting in the long lasting enhancement of evoked glutamate release. Whereas P-type Ca2+ channels are of primary importance in mossy fiber synaptic transmission, both the induction and expression of mossy fiber LTP can occur in the absence of P-type (or N-type) Ca2+ channels.

Animals↗
PubMed1994

Synaptic augmentation by 5-HT at rested Aplysia sensorimotor synapses: independence of action potential prolongation.

Short-term augmentation of synaptic transmission at sensory neuron synapses of Aplysia contributes to behavioral sensitization and is one of the current models for a cellular mechanism of learning. This neuromodulatory process, mediated at least in part by the facilitatory neurotransmitter serotonin (5-HT) acting through cAMP, has been thought to result largely from prolongation of the sensory neuron action potential (AP). The quantitative contribution of AP prolongation to synaptic augmentation was examined using a new culture preparation that is favorable for controlling the voltage at the presynaptic terminals. Preventing AP prolongation by using unvarying voltage-clamp commands in place of triggered APs did not reduce augmentation significantly, and pharmacological prolongation of APs caused by a high concentration of 5-HT led to a negligible increase in the synaptic response. Together with earlier evidence against the involvement of changes in Ca2+ current, these results suggest that synaptic augmentation may result from modulation of steps in the secretory process that lie distal to the flow of ion currents across the nerve terminal membrane.

Action Potentials↗
PubMed1995

Patch sensor detection of glutamate release evoked by a single electrical shock.

We tried to detect minimal stimulation-induced glutamate overflow from the surface of a hippocampal slice using an outside-out patch electrode excised from pyramidal cell membranes. The amplitude of the stimulation-induced patch current was dependent on the distance between the slice surface and the tip of patch sensor. The current-voltage relations of the stimulation-induced patch current were similar to those of the current evoked puff by application of L-glutamate to the patch. This indicates that the stimulation-induced patch current was produced by glutamate released from presynaptic terminals, and thus this technique may be useful in the study of transmitter release evoked by minimal electrical stimulation in brain slices.

Action Potentials↗
PubMed1995

The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system.

Non-A beta component of Alzheimer's disease amyloid (NAC) is the second component in the amyloid from brain tissue of patients affected with Alzheimer's disease. Its precursor protein (NACP) was shown to be a brain-specific protein. In rat brain, NACP was more abundant in the neocortex, hippocampus, olfactory bulb, striatum, thalamus, and cerebellum and less abundant in the brain stem. Confocal laser microscopy analysis revealed that anti-NACP immunostaining was colocalized with synaptophysin-immunoreactive presynaptic terminals. Ultrastructural analysis showed that NACP immunoreactivity was associated with synaptic vesicles. NACP sequence showed 95% identity with that of rat synuclein 1, a synaptic/nuclear protein previously identified in rat brain, and good homology with Torpedo synuclein from the electric organ synapse and bovine phosphoneuroprotein 14 (PNP-14), a brain-specific protein present in synapses. Therefore, NACP is a synaptic protein, suggesting that synaptic aberration observed in senile plaques might be involved in amyloidogenesis in Alzheimer's disease.

Alzheimer Disease↗
PubMed1990

Transplantation of embryonic olive in the climbing-fiber-deprived adult rat cerebellum: synaptogenesis on host Purkinje dendritic spines by donor climbing fibers.

Synaptic formation by donor climbing fibers on the host Purkinje spines was observed in our experiments. In the adult rat cerebellum where the inferior olive and climbing fibers had been destroyed by intraperitoneal injection of 3-acetylpyridine, the medullary embryonic 14-16-day (E14-E16) tissue containing the olive was grafted. After 3 weeks, climbing-fiber-type preterminals bearing closely-packed round vesicles were found that established synaptic contacts on dendritic spines of the host Purkinje cells. Quantitative analysis indicates the increment of newly-formed climbing presynaptic terminals, the number of which was statistically significant (P less than 0.01).

Afferent Pathways↗
PubMed1991

Pharmacological evidence for an omega-conotoxin, dihydropyridine-insensitive neuronal Ca2+ channel.

Inactivation of N-type voltage-sensitive Ca2+ channels (VSCC) with omega-conotoxin (omega-CgTx) in tissue obtained from chicken brain produces a concentration dependent (0.01-0.1 microM) inhibition of K(+)-stimulated Ca2+ influx (delta K+), the rise in [Ca2+]i and acetylcholine (ACh) release. In identical preparations from rat brain, Ca2+ influx and the rise in [Ca2+]i were only marginally affected by much higher (1-10 microM) concentrations of omega-CgTx. The release of ACh, however, was inhibited to the same degree with similar amounts of omega-CgTx as those used in chicken brain. An L-type VSCC inhibitor failed to affect any of these parameters alone, or to augment the effect of omega-CgTx. The results suggest that almost all the VSCC in chicken brain are of the N type and that these channels regulate neurotransmitter release. In rat brain, on the other hand, Ca2+ channels resistant to N- or L-type blockers account for almost 75% of the measurable Ca2+ influx and rise in [Ca2+]i. The conspicuous dissociation between the regulation of Ca2+ influx and ACh release demonstrated in rat brain by using omega-CgTx, suggest that neurotransmitter release is governed by only a small proportion of strategically located N-type, omega-CgTx sensitive, VSCC in the presynaptic terminal.

Acetylcholine↗
PubMed1996

Retrograde messengers and long-term potentiation: a progress report.

Long term potentiation (LTP) is a widely studied form of synaptic plasticity. Brief tetanic stimulation of synaptic afferents in several areas of the brain, most notably the hippocampus, produces long lasting changes in the synaptic strength. The induction of LTP requires in the limit a significant activation of the NMDA receptor and the subsequent entry of calcium into the post synaptic cell. The maintenance of LTP requires at least in part a change in presynaptic function. This review addresses the current thinking in the literature on how a post synaptic induction event may be communicated to the presynaptic terminal and subsequently lead to a series of poorly defined biochemical process that ultimately lead to an enhancement in the efficiency of the potentiated terminal.

Animals↗
PubMed1991

Further studies on the biochemical characterization and autoradiographic distribution of [3H]hemicholinium-3 binding sites in rat brain: a presynaptic cholinergic marker.

Hemicholinium-3 (HC-3) is a potent inhibitor of the high-affinity choline uptake system (HACU). Here we report on the biochemical characterization and autoradiographic distribution of [3H]hemicholinium-3 binding sites in rat brain, confirming and expanding results from previous studies. The binding of [3H]HC-3 to striatal membranes was specific, to a single site, sodium-dependent, saturable, and of high-affinity, Kd values being about 3 nM for striatum, 5 nM for the hippocampus and 12 nM for neocortex. [3H]HC-3 specific binding exhibited a pharmacological profile suggestive of physiologically relevant interactions and fully comparable to that reported for HACU. The uneven distribution of [3H]HC-3 binding sites exhibited a high degree of correspondence with the reported distribution of HACU and other enzymatic presynpatic cholinergic markers. The punctual differences between our study and previous works on [3H]HC-3 binding are analysed. We conclude that [3H]HC-3 labelling may be used as a selective and quantifiable marker of the cholinergic presynaptic terminals in close relationship with HACU.

Animals↗
PubMed1995

Mathematic modelling of the enteric nervous network. 5. Excitation propagation in a planar neural network.

A mathematical model of the enteric nervous system (Auerbach's plexus) as a planar neural network has been developed, based on the actual morphological data of its organization. The network is composed of excitatory (cholinergic) and inhibitory (adrenergic) neurones interconnected by polysynaptic channels, formed of the geometrically non-uniform unmyelinated nerve axons. The synaptic zones are modelled as a three-compartment open pharmacokinetics system, i.e., presynaptic terminal, synaptic cleft and postsynaptic membrane where the pharmacokinetic mechanisms of electrochemical coupling are considered. All the chemical reactions of transformation of acetylcholine and adrenaline within them are described by first order Michaelis-Menten kinetics. The propagation of the electrical impulse along the pathways and in the vicinity of the nerve terminal is described by the modified Hodgkin-Huxley equations. The results of numerical simulation of the propagation of excitation within the neuronal chain, inhibitory feedback circuit, and a planar neuronal network under normal physiological conditions and after treatment with cholinergic/adrenergic agonists and antagonists are presented. The model predicts the dose-dependent influence of pharmacological agents on the neural network function.

Action Potentials↗
PubMed1975

Snyaptic and dendritic development and mental defect.

The hypothesis that specific defects in synaptic and dendritic development of cerebral cortex may form the anatomical basis in some cases of mental defect has been examined by electron microscopy and by use of the Golgi-Cos method. Two types of abnormality have been identified to date. One is a specific lesion of presynaptic terminals, first reported by Gonatas and Goldensohn (14) in a child with mental retardation and myoclonic seizures. This lesion, consisting of massive proliferation of membranous structures in terminal axons, appears to be rare and may be the anatomical substrate of one or more genetically determined dementing illnesses in infancy. More commonly, cerebral cortex from the severely retarded shows defects in number, length, and spatial arrangement of dendrites and synapses, best demonstrated by the Golgi method. Such abnormalities have been found in six out of eleven brains from severely retarded individuals examined by us. The etiology of the retardation was unknown in the majority; two had other recognizable developmental malformations of brain. It is suggested that a number of different etiological factors, if active during the period of rapid synaptic and dendritic growth in cerebral cortex (i. e., from the last trimester of pregnancy to the end of the first postnatal year) may result in stunted development of these structures.

Child↗
PubMed2005

Alpha-synuclein-positive structures induced in leupeptin-infused rats.

Abnormal accumulation of alpha-synuclein is regarded as a key pathological step in a wide range of neurodegenerative processes, not only in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) but also in multiple-system atrophy (MSA). Nevertheless, the mechanism of alpha-synuclein accumulation remains unclear. Leupeptin, a protease inhibitor, has been known to cause various neuropathological changes in vivo resembling those of aging or neurodegenerative processes in the human brain, including the accumulation of neuronal processes and neuronal cytoskeletal abnormalities leading to neurofibrillary tangle (NFT)-like formations. In the present study, we administered leupeptin into the rat ventricle and found that alpha-synuclein-positive structures appeared widely in the neuronal tissue, mainly in neuronal processes of the fimbria and alveus. Immunoelectron microscopic study revealed that alpha-synuclein immunoreactivity was located in the swollen axons of the fimbria and alveus, especially in the dilated presynaptic terminals. In addition colocalization of alpha-synuclein with ubiquitin was rarely observed in confocal laser-scan image. This is the first report of experimentally induced in vivo accumulation of alpha-synuclein in non-transgenic rodent brain injected with a well-characterized protease inhibitor by an infusion pump. The present finding suggests that the local accumulation of alpha-synuclein might be induced by the impaired metabolism of alpha-synuclein, which are likely related to lysosomal or ubiquitin-independent proteasomal systems.

Animals↗
PubMed2006

Calcium microdomains in regulated exocytosis.

Katz and co-workers showed that Ca(2+) triggers exocytosis. The existence of sub-micrometer domains of greater than 100 microM [Ca(2+)](i) was postulated on theoretical grounds. Using a modified, low-affinity aequorin, Llinas et al. were the first to demonstrate the existence of Ca(2+) 'microdomains' in squid presynaptic terminals. Over the past several years, it has become clear that individual Ca(2+) nano- and microdomains forming around the mouth of voltage-gated Ca(2+) channels ascertain the tight coupling of fast synaptic vesicle release to membrane depolarization by action potentials. Recent work has established different geometric arrangements of vesicles and Ca(2+) channels at different central synapses and pointed out the role of Ca(2+) syntillas - localized, store operated Ca(2+) signals - in facilitation and spontaneous release. The coupling between Ca(2+) increase and evoked exocytosis is more sluggish in peripheral terminals and neuroendocrine cells, where channels are less clustered and Ca(2+) comes from different sources, including Ca(2+) influx via the plasma membrane and the mobilization of Ca(2+) from intracellular stores. Finally, also non- (electrically) excitable cells display highly localized Ca(2+) signaling domains. We discuss in particular the organization of structural microdomains of Bergmann glia, specialized astrocytes of the cerebellum that have only recently been considered as secretory cells. Glial microdomains are the spatial substrate for functionally segregated Ca(2+) signals upon metabotropic activation. Our review emphasizes the large diversity of different geometric arrangements of vesicles and Ca(2+) sources, leading to a wide spectrum of Ca(2+) signals triggering release.

Action Potentials↗
PubMed2005

Synaptic protein degradation by the ubiquitin proteasome system.

Synaptic plasticity -- the modulation of synaptic strength between a presynaptic terminal and a postsynaptic dendrite -- is thought to be a mechanism that underlies learning and memory. It has become increasingly clear that regulated protein synthesis is an important mechanism used to regulate the protein content of synapses that results in changes in synaptic strength. Recent experiments have highlighted a role for the opposing process, that is, regulated protein degradation via the ubiquitin-proteasome system, in synaptic plasticity. These recent findings raise exciting questions as to how proteasomal activity can regulate synapses over different temporal and spatial scales.

Animals↗
PubMed2005

Area-specific effects of brain-derived neurotrophic factor (BDNF) genetic ablation on various neuronal subtypes of the mouse brain.

The effects of brain-derived neurotrophic factor (BDNF) on the development of presynaptic terminals and of neuronal subtypes in various brain areas were studied in BDNF-knockout (BDNF-/-) mice at postnatal days 15-17. Western analysis revealed no changes in the overall amount of a variety of synaptic proteins in BDNF-/- mice as compared to wild type mice. In addition, the complex between the vesicular proteins, synaptophysin and synaptobrevin, as well as their respective homodimers were unaltered. Moreover, no changes in the density of neurons were found in, e.g., the CA3 region of the hippocampus and the nucleus nervi facialis of BDNF-/- mice. However, cholinergic cells were reduced by 20% in the medial septum of BDNF-/- mice associated with a decrease in the activity of choline acetyltransferase and protein levels of nerve growth factor in the hippocampus by 16% and 44%, respectively. In the striatum, however, the total number of cholinergic cells were comparable in both groups, although the activity of choline acetyltransferase was decreased by 46%. In GABAergic interneurons, the expression of neuropeptides in various brain areas was differentially affected by BDNF deletion as revealed by immunohistochemistry. In the hippocampus and cortex of BDNF-/- mice, the density of neuropeptide Y-, somatostatin-, and parvalbumin-immunoreactive cells was drastically reduced, whereas the density of calretinin-positive cells was increased. The extent of these changes in neuropeptide-containing cells varied among hippocampal subregions. In the striatum, only the density of parvalbumin-immunoreactive cells was decreased by approximately 45%. In conclusion, BDNF deficiency is accompanied by a differential dysregulation in the expression of neuropeptides and calcium-binding proteins in otherwise intact GABAergic and glutamatergic neurons in a region-specific manner.

Age Factors↗
PubMed2004

Molecular physiology of P2 receptors in the central nervous system.

Neurons of the central nervous system (CNS) are endowed with ATP-sensitive receptors belonging to the P2X (ligand-gated cationic channels) and P2Y (G protein-coupled receptors) types. Whereas a number of P2X receptors mediate fast synaptic responses to the transmitter ATP, P2Y receptors mediate either slow changes of the membrane potential in response to non-synaptically released ATP or the interaction with receptors for other transmitters. To date seven P2X and seven P2Y receptors of human origin have been molecularly identified and functionally characterized. P2X subunits may occur as homooligomers or as heterooligomeric assemblies of more than one subunit. P2X(7) subunits do not form heterooligomeric assemblies and are unique in mediating apoptosis and necrosis of glial cells and possibly also of neurons. The P2X(2), P2X(4), P2X(4)/P2X(6) and P2Y(1) receptors appear to be the predominant neuronal types. The localisation of these receptors may be at the somato-dendritic region (postsynaptic) or at the nerve terminals (presynaptic). Postsynaptic P2 receptors appear to be mostly excitatory, while presynaptic P2 receptors may be either excitatory (P2X) or inhibitory (P2Y). Since in the CNS the stimulation of a single neuron may activate multiple networks, a concomitant stimulation of facilitatory and inhibitory circuits as a result of ATP release is also possible. Finally, the enzymatic degradation of ATP may lead to the local generation of adenosine which can modulate via A(1) or A(2A) receptor-activation the ATP effect.

Adenosine Triphosphate↗
PubMed2006

Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion.

"Free Zn2+" (rapidly exchangeable Zn2+) is stored along with glutamate in the presynaptic terminals of specific specialized (gluzinergic) cerebrocortical neurons. This synaptically releasable Zn2+ has been recognized as a potent modulator of glutamatergic transmission and as a key toxin in excitotoxic neuronal injury. Surprisingly (despite abundant work on bound zinc), neither the baseline concentration of free Zn2+ in the brain nor the presumed co-release of free Zn2+ and glutamate has ever been directly observed in the intact brain in vivo. Here, we show for the first time in dialysates of rat and rabbit brain and human CSF samples from lumbar punctures that: (i) the resting or "tonic" level of free Zn2+ signal in the extracellular fluid of the rat, rabbit and human being is approximately 19 nM (95% range: 5-25 nM). This concentration is 15,000-fold lower than the "300 microM" concentration which is often used as the "physiological" concentration of free zinc for stimulating neural tissue. (ii) During ischemia and reperfusion in the rabbit, free zinc and glutamate are (as has often been presumed) released together into the extracellular fluid. (iii) Unexpectedly, Zn2+ is also released alone (without glutamate) at a variable concentration for several hours during the reperfusion aftermath following ischemia. The source(s) of this latter prolonged release of Zn2+ is/are presumed to be non-synaptic and is/are now under investigation. We conclude that both Zn2+ and glutamate signaling occur in excitotoxicity, perhaps by two (or more) different release mechanisms.

Anesthetics↗