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PubMed1975

The distribution of acetylcholine sensitivity at the post-synaptic membrane of vertebrate skeletal twitch muscles: iontophoretic mapping in the micron range.

1. The distribution of acetylcholine (ACh) sensitivity was mapped in skeletal twitch muscles of the snake, frog and mudpuppy with iontophoretic methods that provide a resolution in the mum range. 2. The preparations were thin sheets of muscle fibres that were viewed with Nomarski optics, giving sharp definition of cellular detail. The muscles in the snake were especially suitable. Their motor nerves terminate in a compact cluster of synaptic boutons that rest in distinct craters on the muscle surface. After treatment with collagenase the motor nerve and its terminal boutons can be removed, exposing the subsynaptic membrane in the craters. 3. The slopes of dose-response curves obtained by iontophoretic application of ACh were expressed in mV/nC and used as an index of ACh sensitivity. The areas of highest sensitivity, tested either with the terminals in place or removed, were those immediately under the presynaptic terminals. The greatest subsynaptic sensitivities were about 5000 mV/nC, and the time course of the potentials caused by ACh released iontophoretically closely matched that of synaptic potentials set up by ACh released by the nerve. 4. The sensitivity of the extrasynaptic surface less than 2 mum away was at least 50 times lower than that of the subsynaptic membrane. The low extrasynaptic sensitivity declined still further at greater distances. 5. Acetylcholinesterase was shown physiologically to be confined to subsynaptic areas. No activity of the enzyme was detected in extrasynaptic areas beyond about 2 mum from the edge of the synapse. 6. The confinement of high densities of receptors and of acetylcholinesterase to the subsynaptic membrane in muscles is also a feature in parasympathetic neurones. It is suggested that similar specialization may be a widespread property of neurones with chemical synapses.

Acetylcholine↗
PubMed2001

Dopamine D(2)-like receptors selectively block N-type Ca(2+) channels to reduce GABA release onto rat striatal cholinergic interneurones.

1. The modulatory roles of dopamine (DA) in inhibitory transmission onto striatal large cholinergic interneurones were investigated in rat brain slices using patch-clamp recording. 2. Pharmacologically isolated GABA(A) receptor-mediated IPSCs were recorded by focal stimulation within the striatum. Bath application of DA reversibly suppressed the amplitude of evoked IPSCs in a concentration-dependent manner (IC(50), 10.0 microM). 3. A D(2)-like receptor agonist, quinpirole (3-30 microM), also suppressed the IPSCs, whereas a D(1)-like receptor agonist, SKF 81297, did not affect IPSCs. Sulpiride, a D(2)-like receptor antagonist, blocked the DA-induced suppression of IPSCs (apparent dissociation constant (K(B)), 0.36 microM), while a D(1)-like receptor antagonist, SCH 23390 (10 microM), had no effect. 4. DA (30 microM) reduced the frequency of spontaneous miniature IPSCs (mIPSCs) without changing their amplitude distribution, suggesting that GABA release was inhibited, whereas the sensitivity of postsynaptic GABA(A) receptors was not affected. The effect of DA on the frequency of mIPSCs was diminished when extracellular Ca(2+) was replaced by Mg(2+) (5 mM), indicating that DA affected the Ca(2+) entry into the presynaptic terminal. 5. An N-type Ca(2+) channel selective blocker, omega-conotoxin GVIA (omega-CgTX, 3 microM), suppressed IPSCs by 65.4 %, whereas a P/Q-type Ca(2+) channel selective blocker, omega-agatoxin IVA (omega-Aga-IVA, 200 nM), suppressed IPSCs by 78.4 %. Simultaneous application of both blockers suppressed IPSCs by 95.9 %. Assuming a 3rd power relationship between Ca(2+) concentration and transmitter release, the contribution of N-, P/Q- and other types of Ca(2+) channels to presynaptic Ca(2+) entry is estimated to be, respectively, 29.8, 40.0 and 34.5 % at this synapse. After the application of omega-CgTX, DA (30 microM) no longer affected IPSCs. In contrast, omega-Aga-IVA did not alter the level of suppression by DA, suggesting that the action of DA was selective for N-type Ca(2+) channels. 6. A G protein alkylating agent, N-ethylmaleimide (NEM), significantly reduced the DA-induced suppression of IPSCs. 7. These results suggest that presynaptic D(2)-like receptors are present on the terminals of GABAergic afferents to striatal cholinergic interneurones, and down-regulate GABA release by selectively blocking N-type Ca(2+) channels through NEM-sensitive G proteins.

Animals↗
PubMed2006

Cortical choline transporter function measured in vivo using choline-sensitive microelectrodes: clearance of endogenous and exogenous choline and effects of removal of cholinergic terminals.

The capacity of the high-affinity choline transporter (CHT) to import choline into presynaptic terminals is essential for acetylcholine synthesis. Ceramic-based microelectrodes, coated at recording sites with choline oxidase to detect extracellular choline concentration changes, were attached to multibarrel glass micropipettes and implanted into the rat frontoparietal cortex. Pressure ejections of hemicholinium-3 (HC-3), a selective CHT blocker, dose-dependently reduced the uptake rate of exogenous choline as well as that of choline generated in response to terminal depolarization. Following the removal of CHTs, choline signal recordings confirmed that the demonstration of potassium-induced choline signals and HC-3-induced decreases in choline clearance require the presence of cholinergic terminals. The results obtained from lesioned animals also confirmed the selectivity of the effects of HC-3 on choline clearance in intact animals. Residual cortical choline clearance correlated significantly with CHT-immunoreactivity in lesioned and intact animals. Finally, synaptosomal choline uptake assays were conducted under conditions reflecting in vivo basal extracellular choline concentrations. Results from these assays confirmed the capacity of CHTs measured in vivo and indicated that diffusion of substrate away from the electrode did not confound the in vivo findings. Collectively, these results indicate that increases in extracellular choline concentrations, irrespective of source, are rapidly cleared by CHTs.

Animals↗
PubMed1995

Novel pharmacological sensitivity of the presynaptic calcium channels controlling acetylcholine release in skate electric organ.

The presynaptic terminals of skate (Raja montagui) electric organ were tested for their sensitivity to calcium channel antagonists. Acetylcholine (ACh) release and the elevation of intraterminal Ca2+ concentrations triggered by K+ depolarisation were studied. ACh release was measured as 3H efflux from slices of organ prelabelled with [3H]choline. Depolarisation caused a marked, Ca(2+)-dependent increase in 3H efflux that was completely blocked by 100 microM Cd2+ and by 300 nM omega-conotoxin-MVIIC (MVIIC). Inhibition by MVIIC was concentration dependent (IC50 of approximately 20 nM) and reversible. No inhibition was seen with nifedipine (5 microM) or the two other peptide antagonists studied: omega-conotoxin-GVIA (GVIA) at 5 microM and omega-agatoxin-IVA (Aga-IVA) at 1 microM. In a "nerve plate" preparation (a presynaptic plexus of nerve fibres, Schwann cells, and nerve terminals) changes in intraterminal Ca2+ concentrations were measured by microfluorimetry using fluo-3. An increase in fluorescence, indicating a rise in the free [Ca2+], rapidly followed K+ depolarisation, and this change was restricted to the nerve terminals. This response was insensitive to nifedipine (5 microM), GVIA (5 microM), and Aga-IVA (300 nM) but almost completely abolished by MVIIC (1 microM). MVIIC inhibition was concentration dependent and partially reversible. These results show that the nerve terminals in skate electric organ have calcium channels with a pharmacological sensitivity that is markedly different from the established L, N, and P types in other systems but shares some, but not all, of the features of the recently described Q type.

Acetylcholine↗
PubMed1994

Molecular pathways for presynaptic calcium signaling.

The results presented in this article describe two distinct, Ca-regulated molecular pathways in presynaptic terminals and implicate these two pathways in differentially mediating neurotransmitter secretion and PTP. Our current view of the Ca-dependent triggering of secretion and PTP is shown in Fig. 9. According to this scheme, differential activation of these two pathways is achieved by a combination of diffusion-based dilution of Ca that enters the terminal through voltage-gated Ca channels and by coupling these pathways to Ca receptors with different affinities for Ca ions. A simple way to achieve these conditions is to position these two receptors at different distances from the Ca channels, as shown in Fig. 2. Given that Ca ions are involved in activating many different presynaptic processes (Fig. 1), we propose that closer scrutiny of the molecular physiology of nerve terminals will reveal a wide variety of Ca-activated pathways responsible for producing these diverse processes.

Amino Acid Sequence↗
PubMed2007

Presynaptic Ca2+ buffers control the strength of a fast post-tetanic hyperpolarization mediated by the alpha3 Na(+)/K(+)-ATPase.

The excitability of CNS presynaptic terminals after a tetanic burst of action potentials is important for synaptic plasticity. The mechanisms that regulate excitability, however, are not well understood. Using direct recordings from the rat calyx of Held terminal, we found that a fast Na(+)/K(+)-ATPase (NKA)-mediated post-tetanic hyperpolarization (PTH) controls the probability and precision of subsequent firing. Notably, increasing the concentration of internal Ca(2+) buffers or decreasing Ca(2+) influx led to larger PTH amplitudes, indicating that an increase in [Ca(2+)](i) regulates PTH via inhibition of NKAs. The characterization for the first time of a presynaptic NKA pump current, combined with immunofluorescence staining, identified the alpha3-NKA isoform on calyx terminals. Accordingly, the increased ability of the calyx to faithfully fire during a high-frequency train as it matures is paralleled by a larger expression of alpha3-NKA during development. We propose that this newly discovered Ca(2+) dependence of PTH is important in the post-burst excitability of nerve terminals.

Action Potentials↗
PubMed1990

Histamine and FLRFamide regulate acetylcholine release at an identified synapse in Aplysia in opposite ways.

1. The effects of histamine and FLRFamide (Phe-Leu-Arg-Phe-NH2) on acetylcholine (ACh) release were studied in the buccal ganglion of Aplysia californica on an identified synapse (buccal ganglion inhibitory synapse, BGIS) involved in a small neuronal circuit controlling the feeding behaviour. The inhibitory postsynaptic current (IPSC) evoked by a presynaptic spike in the voltage-clamped postsynaptic neurone was decreased by histamine and increased by FLRFamide. 2. Histamine and FLRFamide modified the amplitude of the presynaptic spike. To test if these drugs acted directly on presynaptic calcium influx, we evoked transmitter release by 3 s depolarizations of the presynaptic neurone (to +10 mV) under voltage clamp to avoid modifications of presynaptic membrane polarization induced by changes in presynaptic voltage-dependent K+ and/or Na+ conductances. 3. Statistical analysis of this evoked long-duration (3 s) induced postsynaptic current (LDIPSC) allowed us to calculate the amplitude and the decay time of the miniature postsynaptic current and consequently the number of quanta released by the presynaptic terminal. 4. The amplitude of the LDIPSC decreased during the 3 s presynaptic depolarization. This was not due to a lack of available transmitter, since LDIPSC amplitude could be maintained constant by a 'clamp of the release of ACh' which adequately depolarized the presynaptic neurone, but rather to changes in the calcium influx into the presynaptic neurone. 5. FLRFamide increased more the initial portions of the LDIPSC than the final portions. This effect of FLRFamide was only reduced and delayed by atropine or curare, antagonists of muscarinic-like and nicotinic-like autoreceptors previously demonstrated to be present at the same terminal. Activation of the nicotinic-like receptors, which also increased transmitter release, induced a modification of the shape of the LDIPSC which was completely different from that due to FLRFamide. 6. Histamine decreased the amplitude of the LDIPSC. This effect was more pronounced at the beginning of the response. The effects of histamine were insensitive to curare and atropine, but were completely blocked by cimetidine, a specific histamine receptor antagonist. 7. The modifications of the shape and of the amplitude of the LDIPSC by FLRFamide and histamine suggested that these molecules alter presynaptic influx of calcium. This was confirmed by the analysis of calcium current recorded from the presynaptic neurone: the calcium inward current in the presynaptic neurone was increased by FLRFamide and reduced by histamine, whereas the activation of autoreceptors had no measurable effect on calcium current.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1979

Filamentous contacts containing subjunctional dense lattice and tubular smooth endoplasmic reticulum in cat lateral geniculate nuclei.

Ultrastructure of filamentous contacts was examined in the cat lateral geniculate nucleus. This intercellular contact was classified into two types, asymmetrical and symmetrical, according to its fine structure. (1) The asymmetrical filamentous contact had a different fine structure on the cytoplasmic sides of its apposed membranes. This sort of contact occurred between the postsynaptic components of principal cells and the presynaptic terminals of either optic nerve or interneurons. The membrane on the presynaptic side showed a wavy outline. Plaques of cytoplasmic density were located on the crests of the wave. On the postsynaptic side cytoplasmic dense material formed a regularly arranged latticework on the membrane, 'subjunctional dense lattice'. The dense lattice was closely associated with underlying smooth surfaced endoplasmic reticulum and mitochondria, so as to form a subjunctional complex consisting of these 3 organelles. Two filamentous structures, neurofilaments and microtubules, enter and leave this subjunctional complex. (2) The symmetrical filamentous contact occurred between two principal cell components. Nearly the same fine structural arrangement as that on the postsynaptic side of the asymmetrical contact was present in the cytoplasm on the both sides of this junction.

Animals↗
PubMed2000

Synaptic localization and presynaptic function of calcium channel beta 4-subunits in cultured hippocampal neurons.

Neurotransmitter release is triggered by the influx of Ca(2+) into the presynaptic terminal through voltage gated Ca(2+)-channels. The shape of the presynaptic Ca(2+) signal largely determines the amount of released quanta and thus the size of the synaptic response. Ca(2+)-channel function is modulated in particular by the auxiliary beta-subunits that interact intracellularly with the pore-forming alpha(1)-subunit. Using retrovirus-mediated gene transfer in cultured hippocampal neurons, we demonstrate that functional GFP-beta(4) constructs colocalize with the synaptic vesicle marker synaptobrevin II and endogenous P/Q-type channels, indicating that beta(4)-subunits are localized to synaptic sites. Costaining with the dendritic marker MAP2 revealed that the beta(4)-subunit is transported to dendrites as well as axons. The nonconserved amino- and carboxyl-termini of the beta(4)-subunit were found to target the protein to the synapse. Physiological measurements in autaptic hippocampal neurons infected with green fluorescent protein (GFP)-beta(4) revealed an increase in both excitatory post-synaptic current amplitude and paired pulse facilitation ratio, whereas the GFP-beta(4) mutant, GFP-beta(4)(Delta50-407), which demonstrated a cytosolic localization pattern, did not alter these synaptic properties. In summary, our data suggest a pre-synaptic function of the Ca(2+)-channel beta(4)-subunit in synaptic transmission.

Base Sequence↗
PubMed2004

Distinct properties of presynaptic group II and III metabotropic glutamate receptor-mediated inhibition of perforant pathway-CA1 EPSCs.

I have compared the effects of group II or III metabotropic glutamate receptor (mGluR) activation on monosynaptic excitatory responses recorded intracellularly from CA1 pyramidal neurons of rat hippocampus and evoked by perforant pathway stimulation in vitro. The excitatory postsynaptic currents (EPSCs) were reduced either by the group II mGluR agonist LY354740 (500 nM, 31 +/- 6% of control) or by the group III agonist L-AP4 (400 microM, 53 +/- 5% of control). Both drugs enhanced EPSC paired-pulse facilitation (range 125-189% of control). These effects were blocked by the broad-spectrum mGluR antagonist LY341495 (1 or 20 microM) which when applied alone did not significantly change the EPSCs elicited at low (0.1-0.2 Hz) or higher (1-100 Hz) frequency of stimulation. Prior reduction of the EPSCs induced by L-AP4 did not occlude the subsequent inhibition elicited by LY354740. The effect of LY354740, but not that of L-AP4, was blocked in the presence of the cAMP analogue Sp-cAMPS (20 microM) and with the K(+) channel antagonist alpha-dendrotoxin (125 nM). In contrast, the effect of L-AP4, but not that of LY354740, was prevented by the calmodulin inhibitor ophiobolin A (25 microM) and with the N-type Ca(2+) channel antagonist omega-conotoxin-GVIA (1 microM). In the presence of the P/Q type Ca(2+) channel antagonist omega-agatoxin-IVA (400 nM), the EPSCs were depressed either by LY354740 or by L-AP4. Groups II and III mGluRs are segregated at the presynaptic terminal, and there are distinct differences between the properties of the presynaptic inhibition mediated by these two groups of receptors.

Amino Acids↗
PubMed1976

Synaptic transmission in the sixth ganglion of the cockroach: action of 4-aminopyridine.

1. Study was made of the action of 4-aminopyridine (5 X 10(-5) M) on synaptic transmission in the last abdominal ganglion of Periplaneta americana. The 'oil-gap' technique was used to record postsynaptic events in a single giant axon. 2. 4-AP quickly increased the 'background' of postsynaptic activity, which consisted of 'spontaneous' unitary EPSPs and IPSPs. Postsynaptic spikes were also propagated. 3. Both evoked EPSPs (stimulation of cercal nerve XI) and evoked IPSPs (stimulation of cercal nerve X) were greatly increased in amplitude although their duration (half-time) was unaltered. 4. 4-AP triggered presynaptic action potentials in the cercal nerves (recorded with external electrodes). These 'antidromic' potentials appeared singly or sometimes repetitively, especially after electrical stimulation of the cercal nerves. They were often in monosynaptic correlation with unitary EPSPs. 5. Neither the resting potential nor the postsynaptic membrane resistance was modified. 6. There were no changes in the equilibrium potentials of the ions involved in postsynaptic events. 7. The results may be essentially explained by an increase in transmitter release after 4-AP treatment, which may be partly the result of a rise in presynaptic terminal excitability, and partly the result of a lengthening of the presynaptic action potentials.

Action Potentials↗
PubMed1991

Variation in terminal morphology and presynaptic inhibition at crustacean neuromuscular junctions.

Synaptic terminals of excitatory and inhibitory neurons supplying muscle fibers in leg muscles of crabs (Pachygrapsus crassipes and Hyas areneus) were investigated with light and electron microscopy. Terminals responsible for large excitatory postsynaptic potentials (EPSPs) at low frequencies of activation had a compact configuration with clusters of terminal boutons radiating from the main axon branch. Terminals responsible for small EPSPs had a more diffuse organization, with boutons often arranged in series along thin axon branches. Inhibitory neurons, when activated, produced both presynaptic and postsynaptic inhibitory effects, with the former being more potent at low frequencies of activation. Presynaptic inhibition was variable in magnitude but was generally strong in fibers with large EPSPs. Representative terminals from regions of strong and weak presynaptic inhibition were identified by activity-dependent uptake of horseradish peroxidase, serially sectioned, and reconstructed from electron micrographs. Both regions were found to contain axo-axonal synapses from inhibitory to excitatory terminals, with a larger number in the region of strong presynaptic inhibition. In addition, axo-axonal synapses were more uniformly distributed in the latter region. The number of inhibitory presynaptic dense bars (active zones) was somewhat higher in the region of weak inhibition, but larger individual dense bars occurred in the region of strong inhibition. Possible factors contributing to the differences in strength of inhibition include: (1) morphology and electrical properties of terminals; and (2) high probability of transmission at a relatively small number of inhibitory synapses during low frequency activation in the region of strong inhibition.

Action Potentials↗
PubMed1999

The action is at the terminal.

The magnocellular neurons of the supraoptic nucleus have been intensively studied because of their unique bursting and phasic activity patterns. While these can be explained in part by intrinsic membrane conductances, it is now also apparent that afferent inputs are important in sculpting and initiating the activity patterns. Modulation of these inputs, therefore, provides a powerful way to regulate magnocellular neuronal activity. The paper by Oliet & Poulain in this issue of The Journal of Physiology provides evidence that adenosine may be such a modulator in that it acts presynaptically in the supraoptic nucleus (SON) to inhibit both excitatory and inhibitory synaptic currents onto magnocellular neurons. Furthermore, the authors were able to demonstrate an action of endogenous adenosine in the slice by blocking, with an A1-type antagonist, a progressive synaptic depression brought about by continuous afferent stimulation at 1 Hz over 2 min or more. This paper therefore adds to a compelling body of evidence that adenosine has transmitter action in the central nervous system (Dunwiddie, 1985). Several aspects of this study deserve comment and raise questions amenable to experimentation. Adenosine was equipotent in inhibiting IPSCs and EPSCs, thereby raising questions as to the consequences of adenosine action on the output of the nucleus. While it could be argued that intense excitatory inputs would be attenuated, the same would be true for inhibition, making the net effect rather minor. One possible effect could be to stabilize activity levels of the postsynaptic cell at levels conducive for the generation of intrinsic voltage-dependent activity patterns. Another possibility is that adenosine is simply acting to reduce overall metabolic activity; since the metabolic consequences of activity in the presynaptic terminal would be similar in excitatory and inhibitory terminals, it may be irrelevant as to the nature of the transmitter. It is also interesting that the maximum inhibition attained in response to adenosine is only 60 % for either excitatory or inhibitory inputs. This is in contrast to such presynaptic modulators as baclofen, acting at GABAB receptors, where there is 100 % attenuation of afferent evoked potentials (Pittman et al. 1998). Whether this is due to a distribution of adenosine receptors on only a limited number of afferent terminals, or whether it reflects a mechanism of action that is only partially effective in reducing the transmitter release is not known. For example, if adenosine receptors were coupled to only a subset of the calcium channels engaged in transmitter release, one might predict that only part of the transmitter release would be inhibited. However, data from the Oliet & Poulain paper indicate that miniature EPSCs and miniature IPSCs are inhibited by adenosine; as most evidence indicates that TTX-resistant spontaneous currents in magnocellular neurons are calcium insensitive, this suggests that adenosine acts downstream of the calcium influx, perhaps by interfering with the transmitter release machinery (reviewed in Wu & Saggau, 1997). It would also be interesting to determine whether the presynaptic A1 receptors identified here display a sensitivity to pertussis toxin pretreatment. While such receptors are known to be G-protein coupled, presynaptic receptors are often insensitive to inhibition by pertussis toxin. The identification of an action of endogenous adenosine required repetitive stimulation, perhaps because reuptake mechanisms at lower frequencies efficiently removed adenosine. The source of this endogenous adenosine is still unknown. While it could be released by a nucleoside transporter from either glial cells or neurons, another possibility is that it may be produced by metabolic breakdown of ATP (Cunha et al. 1998). ATP is known to be released in the SON from noradrenergic afferents (Buller et al. 1996) and there is also some evidence that it may be released from the magnocellu

Adenosine↗
PubMed1996

Localization of the neural calcium-binding protein VILIP (visinin-like protein) in neurons of the chick visual system and cerebellum.

The visinin-like protein (VILIP) is a member of a recently discovered family of calcium sensors specifically expressed in neurons. Family members contain four potential calcium-binding domains commonly referred to as "EF-hand motifs". VILIP interacts in a calcium-dependent manner with the actin-based neuronal cytoskeleton and modulates the phosphorylation of G-protein-coupled receptors, i.e., rhodopsin, in vitro. Here, we have used antisera against VILIP to study its distribution in the chick brain. Immunostaining of subsets of neurons is observed throughout the brain. Generally, the distribution of VILIP coincides well with the distribution of VILIP transcripts as detected previously by in situ hybridization. The most intense expression is detected in the visual system and the cerebellum. In the visual system, neurons of the nuclei of the ascending tecto-fugal pathway are stained, as are the pretectal, isthmic, and oculomotor nuclei. VILIP immunoreactivity is found in cell bodies, dendrites, and synaptic structures. Thus, VILIP appears to be an excellent marker for the characterization of neurons of the visual pathway. In the cerebellum, VILIP immunoreactivity is detected in deep cerebellar nuclei and in a subset of granule cells, Golgi type II cells, basket cells, and stellate cells, whereas it is completely absent from Purkinje cells. Intense punctate staining in the molecular layer suggests that VILIP is transported from deep cerebellar nuclei and from granule cells to the glutamatergic climbing-fiber and parallel-fiber synapses, respectively, both of which terminate on Purkinje-cell dendrites. The localization of VILIP in these presynaptic terminals has been confirmed at the electron-microscopic level.

Animals↗
PubMed1996

LTP of AMPA and NMDA receptor-mediated signals: evidence for presynaptic expression and extrasynaptic glutamate spill-over.

We have addressed the expression of long-term potentiation (LTP) in hippocampal CA1 by comparing AMPA and NMDA receptor-(AMPAR- and NMDAR-) mediated postsynaptic signals. We find that potentiation of NMDAR-mediated signals accompanies LTP of AMPAR-mediated signals, and is associated with a change in variability implying an increase in quantal content. Further, tetanic LTP of NMDAR-mediated signals can be elicited when LTP of AMPAR-mediated signals is prevented. We propose that LTP is mainly expressed presynaptically, and that, while AMPARs respond only to glutamate from immediately apposed terminals, NMDARs also sense glutamate released from terminals presynaptic to neighboring cells. We also find that tetanic LTP increases the rate of depression of NMDAR-mediated signals by the use-dependent blocker MK-801, implying an increase in the glutamate release probability. These findings argue for a presynaptic contribution to LTP and for extrasynaptic spill-over of glutamate onto NMDARs.

Analysis of Variance↗
PubMed2006

Neurotoxic zinc translocation into hippocampal neurons is inhibited by hypothermia and is aggravated by hyperthermia after traumatic brain injury in rats.

Hypothermia reduces excitotoxic neuronal damage after seizures, cerebral ischemia and traumatic brain injury (TBI), while hyperthermia exacerbates damage from these insults. Presynaptic release of ionic zinc (Zn2+), translocation and accumulation of Zn2+ ions in postsynaptic neurons are important mechanisms of excitotoxic neuronal injury. We hypothesized that temperature-dependent modulation of excitotoxicity is mediated in part by temperature-dependent changes in the synaptic release and translocation of Zn2+. In the present studies, we used autometallographic (AMG) and fluorescent imaging of N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining to quantify the influence of temperature on translocation of Zn2+ into hippocampal neurons in adult rats after weight drop-induced TBI. The central finding was that TBI-induced Zn2+ translocation is strongly influenced by brain temperature. Vesicular Zn2+ release was detected by AMG staining 1 h after TBI. At 30 degrees C, hippocampus showed almost no evidence of vesicular Zn2+ release from presynaptic terminals; at 36.5 degrees C, the hippocampus showed around 20% to 30% presynaptic vesicular Zn2+ release; and at 39 degrees C vesicular Zn2+ release was significantly greater (40% to 60%) than at 36.5 degrees C. At 6 h after TBI, intracellular Zn2+ accumulation was detected by the TSQ staining method, which showed that Zn2+ translocation also paralleled the vesicular Zn2+ release. Neuronal injury, assessed by counting eosinophilic neurons, also paralleled the translocation of Zn2+, being minimal at 30 degrees C and maximal at 39 degrees C. We conclude that pathological Zn2+ translocation in brain after TBI is temperature-dependent and that hypothermic neuronal protection might be mediated in part by reduced Zn2+ translocation.

Animals↗
PubMed1997

Spatial heterogeneity of intracellular Ca2+ signals in axons of basket cells from rat cerebellar slices.

1. Using tight-seal whole-cell recording and digital fluorescence imaging, we studied intracellular calcium (Ca2+i) dynamics in cerebellar basket cells, whose dendrites, axon and presynaptic terminals are coplanar, an optimal configuration for simultaneous optical measurements of all functional domains. 2. In Cs(+)-loaded neurones, depolarizing pulses induced large Ca2+i transients in single axonal varicosities and synaptic terminals, contrasting with much weaker signals between varicosities or in the somato-dendritic domain. 3. Axonal branch points consistently displayed [Ca2+]i rises of similar magnitude and time course to those in axonal terminals and varicosities. 4. In biocytin-filled basket cells, varicosity-like swellings were present along the axon including its branch points. Thus, axonal enlargements are not due to fluorescence-induced cell damage. 5. The spatial heterogeneity of Ca2+i signals was also observed in K(+)-loaded cells upon depolarizing trains, suggesting that this behaviour is an intrinsic property of Ca2+i homeostasis in basket cells. 6. We conclude that depolarization of basket cell axons evokes high local Ca2+i signals in synaptic terminals, en passant varicosities and branch points. While high [Ca2+]i in presynaptic structures presumably triggers transmitter release, Ca2+i transients at branch points may control signal transmission in the axonal arborization.

Animals↗
PubMed1985

Somatotopic organization in cat spinal cord segments with fused dorsal horns: caudal and thoracic levels.

We have explored the somatotopic organization of the two cat spinal cord regions where the dorsal horns are fused (i.e., continuous across the midline): the caudal and thoracic segments. We have mapped the low-threshold component of dorsal horn cell receptive fields (RFs) in these segments and have charted the locations of dorsal root low-threshold mechanoreceptive dermatomes. We also have determined the projections of caudal and thoracic dorsal roots to laminae III and IV by using degeneration techniques. The dorsal skin of the tail or thorax is represented laterally, and ventral skin is represented at the midline, in the fused dorsal horns. Many caudal and thoracic dorsal horn units had RFs that crossed the dorsal or ventral midline of the skin; these units were encountered near the edges or the midline, respectively, of the fused dorsal horns. The tail is fully represented within dorsal root dermatomes S3 to Ca5. Roots more caudal than Ca5 represent progressively smaller skin areas of the distal tail. Adjacent dermatomes overlapped 15-65%. Thoracic dermatomes had a nearly vertical orientation; adjacent dermatomes overlapped by 30-75%. Dorsal roots in caudal and thoracic regions have crossed projections to the medial and lateral (but not middle) portions of the contralateral dorsal horn. These crossed projections are a possible anatomical substrate for RFs that cross the ventral or dorsal midline. The dorsal root projection patterns are consistent with those that would be predicted from the dorsal root dermatomes and dorsal horn cell somatotopy, assuming that the presynaptic terminals' somatotopy is in register with that of dorsal horn cells (the presynaptic somatotopy hypothesis; see Ref. 12).

Animals↗