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PubMed2001

Expression of the Kv3.1 potassium channel in the avian auditory brainstem.

The Shaw-like potassium channel Kv3.1, a delayed rectifier with a high threshold of activation, is expressed in the time coding nuclei of the bird auditory brainstem. In both barn owls and chickens, Kv3.1 mRNA was expressed in the cochlear nucleus magnocellularis (NM) and the nucleus laminaris (NL). Western blot analysis showed that an antibody raised against the synthetic peptide sequence of rat Kv3.1 (rKv3.1) specifically recognized the same 92 kDa protein bands in both rat and chicken synaptosomal preparations. Immunohistochemical analyses using this anti-rKv3.1 antibody revealed a prominent gradient in Kv3.1 immunoreactivity along the tonotopic axis of the barn owl NM and NL and a less prominent gradient in the chicken. The precise localization of the Kv3.1 immunoproduct was resolved by electron microscopy. In both the owl and the chicken, Kv3.1 was targeted postsynaptically in NM and NL. The major difference in localization of Kv3.1 protein between the two birds was the expression of Kv3.1 in the NM axons and terminals in the region of the barn owl NL. This location of Kv3.1 channels supports its postulated function in reducing the width of action potentials as they invade the presynaptic terminal. The presynaptic localization may be a specialization for enabling neurons in owl NM to transmit high-frequency temporal information with little jitter.

Alternative Splicing↗
PubMed2004

Dysmyelinated lower motor neurons retract and regenerate dysfunctional synaptic terminals.

Axonal degeneration is the major cause of permanent neurological disability in individuals with inherited diseases of myelin. Axonal and neuronal changes that precede axonal degeneration, however, are not well characterized. We show here that dysmyelinated lower motor neurons retract and regenerate dysfunctional presynaptic terminals, leading to severe neurological disability before axonal degeneration. In addition, dysmyelination led to a decreased synaptic quantal content, an indicator of synaptic dysfunction. The amplitude and rise time of miniature endplate potentials were also increased, but these changes were primarily consistent with an increase in the passive membrane properties of the transgenic muscle fibers. Maintenance of synaptic connections should be considered as a therapeutic target for slowing progression of neurological disability in primary diseases of myelin.

Animals↗
PubMed2000

Autoimmunity to munc-18 in Rasmussen's encephalitis.

Rasmussen's encephalitis (RE) is a rare disease of the central nervous system characterized by severe epileptic seizures, progressive degeneration of a single cerebral hemisphere, and autoimmunity directed against glutamate receptor subunit, GluR3. We report here the identification of high-titer autoantibodies directed against munc-18 in the serum of a single patient with RE previously shown to have anti-GluR3 antibodies. Munc-18 is an intracellular protein residing in presynaptic terminals, which is required for secretion of neurotransmitters. These findings are consistent with the possibility of intermolecular epitope spreading between GluR3, a postsynaptic cell surface protein, and munc-18, a presynaptic intracellular protein. Immune attack on these two proteins, which participate at distinct steps of synaptic transmission, could act in an additive or synergistic manner to impair synaptic function and lead to seizures and neuronal death.

Amino Acid Sequence↗
PubMed1998

G-Protein-coupled modulation of presynaptic calcium currents and transmitter release by a GABAB receptor.

Presynaptic GABAB receptors play a regulatory role in central synaptic transmission. To elucidate their underlying mechanism of action, we have made whole-cell recordings of calcium and potassium currents from a giant presynaptic terminal, the calyx of Held, and EPSCs from its postsynaptic target in the medial nucleus of the trapezoid body of rat brainstem slices. The GABAB receptor agonist baclofen suppressed EPSCs and presynaptic calcium currents but had no effect on voltage-dependent potassium currents. The calcium current-EPSC relationship measured during baclofen application was similar to that observed on reducing [Ca2+]o, suggesting that the presynaptic inhibition generated by baclofen is caused largely by the suppression of presynaptic calcium influx. Presynaptic loading of the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDPbetaS) abolished the effect of baclofen on both presynaptic calcium currents and EPSCs. The nonhydrolyzable GTP analog guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) suppressed presynaptic calcium currents and occluded the effect of baclofen on presynaptic calcium currents and EPSCs. Photoactivation of GTPgammaS induced an inward rectifying potassium current at the calyx of Held, whereas baclofen had no such effect. We conclude that presynaptic GABAB receptors suppress transmitter release through G-protein-coupled inhibition of calcium currents.

Animals↗
PubMed2005

CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons.

Cannabinoids have been shown to modulate the inhibitory effect of cholecystokinin-containing GABAergic interneurons in the hippocampus via type 1 cannabinoid receptors (CB1 receptor). Although immunohistochemical studies, using pre-embedding techniques, have demonstrated that these receptors are abundant on GABAergic axon terminals, little is known about their exact location relative to the synapse. Here we used two recently developed antibodies against the CB1 receptor to study this question with the postembedding immunogold method, which allows the quantitative examination of receptor distribution along the axonal membrane, even within the synaptic active zone. CB1 receptor positive terminals target both the dendritic and somatic surface of neurons in the CA1 area of the rat hippocampus. We found no difference between these two populations of terminals either in their CB1 receptor density or in the distribution of receptors on their membrane. Recent studies suggest that endocannabinoids play a role in retrograde signaling at these synapses, i.e. signaling molecules diffuse from the postsynaptic membrane to nearby presynaptic terminals. Therefore, we examined the distribution of CB1 receptors on the terminal membranes. We found that they are rare in the synaptic active zone, but are enriched in the perisynaptic annulus, where they can directly influence synaptic calcium channels. Perisynaptic CB1 receptors represent about one tenth of all CB1 receptors in a terminal. In contrast, CB1 receptors have a lower density on the extrasynaptic membrane of terminals far from the postsynaptic cell. We estimated that these terminals contain exceptionally large numbers of CB1 receptors, i.e. a single axon terminal was usually labeled with more than 450 particles. An unexpected finding was that the density of CB1 receptors was significantly higher on preterminal axons than on synaptic terminals. These observations suggest that endocannabinoid signaling may subserve roles other than simply reducing transmitter release from axon terminals.

Animals↗
PubMed1999

Post-tetanic potentiation of GABAergic IPSCs in cultured rat hippocampal neurones.

1. Dual whole-cell patch-clamp recording was used to investigate post-tetanic potentiation (PTP) of GABAergic IPSCs evoked between pairs of cultured rat hippocampal neurones. Tetanization of the presynaptic neurone at frequencies (f) ranging from 5 to 100 Hz resulted in PTP of the IPSCs. Maximum PTP had a magnitude of 51.6 % just after the stimulus train, and lasted up to 1 min. PTP was shown to be dependent on the number of stimuli in the train, but independent of f at frequencies > or =5 Hz. 2. Blocking postsynaptic GABAA receptors with bicuculline during the tetanus did not affect the expression of PTP, showing that it is a presynaptic phenomenon. PTP was strongly affected by changing [Ca2+]o during the tetanus: PTP was reduced by lowering [Ca2+]o, and increased by high [Ca2+]o. 3. PTP was still present after presynaptic injection of BAPTA or EGTA, or following perfusion of the membrane-permeable ester EGTA-tetraacetoxymethyl ester (EGTA AM, 50 microM). On the other hand, EGTA AM blocked spontaneous, asynchronous IPSCs (asIPSCs), which were often associated with tetanic stimulation. 4. Tetanic stimulation in the presence of 4-aminopyridine (4-AP), which promotes presynaptic Ca2+ influx, evoked sustained PTP of IPSCs in half of the neurones tested. 5. The results indicate that PTP at inhibitory GABAergic synapses is related to the magnitude of presynaptic Ca2+ influx during the tetanic stimulation, leading to an enhanced probability of vesicle release in the post-tetanic period. The increase in [Ca2+]i occurs despite the presence of high-affinity exogenous and endogenous intracellular Ca2+ buffers. That PTP of IPSCs depends on the number, and not the frequency, of spikes in the GABAergic neurone is in accordance with a slow clearing of intracellular Ca2+ from the presynaptic terminals.

Animals↗
PubMed2004

Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals.

Dopamine input to the striatum is required for voluntary motor movement, behavioral reinforcement, and responses to drugs of abuse. It is speculated that these functions are dependent on either excitatory or inhibitory modulation of corticostriatal synapses onto medium spiny neurons (MSNs). While dopamine modulates MSN excitability, a direct presynaptic effect on the corticostriatal input has not been clearly demonstrated. We combined optical monitoring of synaptic vesicle exocytosis from motor area corticostriatal afferents and electrochemical recordings of striatal dopamine release to directly measure effects of dopamine at the level of individual presynaptic terminals. Dopamine released by either electrical stimulation or amphetamine acted via D2 receptors to inhibit the activity of subsets of corticostriatal terminals. Optical and electrophysiological data suggest that heterosynaptic inhibition was enhanced by higher frequency stimulation and was selective for the least active terminals. Thus, dopamine, by filtering less active inputs, appears to reinforce specific sets of corticostriatal synaptic connections.

Afferent Pathways↗
PubMed2001

The development of inhibitory synaptic specializations in the mouse deep cerebellar nuclei.

Using confocal laser scanning microscopy and immunohistochemistry, this study shows the complete morphological development of GABAergic synaptic contacts between Purkinje cells and neurons of the deep cerebellar nuclei of the mouse. Firstly, presynaptic varicosities visualized with antibodies against synaptophysin, synapsin or glutamic acid decarboxylase, were detected when the postsynaptic GABA(A) receptors were not yet aggregated in the membrane but had a diffuse cytoplasmic distribution, which indicated a lead in maturation of presynaptic terminals over target cells. Secondly, receptor aggregates developed suddenly after an initial week of diffuse expression and these clusters matured into more numerous and larger synaptic aggregates. During this postsynaptic maturation, the presynaptic varicosities develop into numerous and well-defined spots. As soon as both pre- and postsynaptic clusters were detectable, these sites are always colocalized. We therefore consider the aggregation of postsynaptic receptor during development as a landmark of synapse formation. Our observations are consistent with a developmental model in which the presynaptic neuron differentiates its axon before the target neuron expresses the mature form of its receptors on the membrane. The presynaptic neuron can therefore instruct the target neuron about the distribution and aggregation of the postsynaptic receptors at the synapse.

Aging↗
PubMed2006

Hierarchical assembly of presynaptic components in defined C. elegans synapses.

The presynaptic regions of axons accumulate synaptic vesicles, active zone proteins and periactive zone proteins. However, the rules for orderly recruitment of presynaptic components are not well understood. We systematically examined molecular mechanisms of presynaptic development in egg-laying synapses of Caenorhabditis elegans, demonstrating that two scaffolding molecules, SYD-1 and SYD-2, have key roles in presynaptic assembly. SYD-2 (liprin-alpha) was previously shown to regulate the size and the shape of active zones. We now show that in syd-1 and syd-2 mutants, synaptic vesicles and numerous other presynaptic proteins fail to accumulate at presynaptic sites. SYD-1 and SYD-2 function cell-autonomously at presynaptic terminals, downstream of synaptic specificity molecule SYG-1. SYD-1 is likely to act upstream of SYD-2 to positively regulate its synaptic assembly activity. These data imply a hierarchical organization of presynaptic assembly, in which transmembrane specificity molecules initiate synaptogenesis by recruiting a few key scaffolding proteins, which in turn assemble other presynaptic components.

Animals↗
PubMed2004

Blockade of presynaptic adenosine A1 receptor responses by nitric oxide and superoxide in rat hippocampus.

Activation of N-methyl-D-aspartate (NMDA) receptors prevents the neuronal responses to adenosine in hippocampal slices. As NMDA receptor activation leads to the generation of nitric oxide (NO) and superoxide, we have examined whether these can modify neuronal responses to adenosine and mediate the actions of NMDA. Field excitatory postsynaptic potentials were recorded in the CA1 region of rat hippocampal slices. Paired-pulse interactions were studied to localize the observed interactions to presynaptic terminals. The NO donors S-nitroso-N-acetylpenicillamine and diethylamine NONOate induced a long-lasting potentiation (NO-induced potentiation) of field excitatory postsynaptic potential slope and significantly prevented the presynaptic inhibitory effect of adenosine or the A1 receptor agonist N6-cyclopentyladenosine selectively with no effect on responses to baclofen. The superoxide-generating system of xanthine/xanthine oxidase also prevented presynaptic responses to adenosine and this effect was prevented by superoxide dismutase (SOD). The guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3a]quinoxalin-1-one (10 microM) prevented NO-induced potentiation and the inhibitory effects of S-nitroso-N-acetylpenicillamine and xanthine/xanthine oxidase on adenosine responses. The inhibitory effect of NMDA on adenosine responses was unchanged by 1H-[1,2,4]-oxadiazolo[4,3a]quinoxalin-1-one, indicating that guanosine-3',5-cyclic monophosphate does not mediate this interaction, although it was partially reduced by SOD, suggesting that superoxide might contribute. The reduction of adenosine responses by electrically-induced long-term potentiation was prevented by NO synthase inhibition or SOD. The results indicate that the presynaptic effects of adenosine at presynaptic sites can be prevented by NO or superoxide but that neither of these individually can fully account for the prevention of adenosine responses by NMDA.

2-Amino-5-phosphonovalerate↗
PubMed1996

Micromolar 4-aminopyridine enhances invasion of a vertebrate neurosecretory terminal arborization: optical recording of action potential propagation using an ultrafast photodiode-MOSFET camera and a photodiode array.

Modulation of the amount of neuropeptide released from a neurosecretory tissue may be achieved by different means. These include alterations in the quantity secreted from each active nerve terminal or in the actual number of terminals activated. From the vertebrate hypothalamus, magnocellular neurons project their axons as bundles of fibers through the median eminence and infundibular stalk to arborize extensively and terminate in the neurohypophysis, where the neurohypophysial peptides and proteins are released into the circulation by a Ca-dependent mechanism. Elevating [Ca2+]o increases the magnitude of an intrinsic optical change in the neurohypophysial terminals that is intimately related to the quantity of neuropeptide released. Similarly, the addition of micromolar concentrations of 4-aminopyridine to the bathing solution enhances this change in large angle light scattering. However, we show here that, while these effects are superficially similar, they reflect different mechanisms of action. Evidence from intrinsic optical signals (light scattering) and extrinsic (potentiometric dye) absorption changes suggests that calcium increases the amount of neuropeptide released from each active terminal in the classical manner, while 4-aminopyridine exerts its secretagogue action by enhancing the invasion of action potentials into the magno-cellular neuron's terminal arborization, increasing the actual number of terminals activated. Physiologically, electrical invasion of the complex terminal arborization in the neurohypophysis may represent an extremely sensitive control point for modulation of peptide secretion. This would be especially effective in a neurohaemal organ like the posterior pituitary, where, in contrast with a collection of presynaptic terminals, the precise location of release is less important than the quantity released.

4-Aminopyridine↗
PubMed2006

Activity-related redistribution of presynaptic proteins at the active zone.

Immunogold labeling distributions of seven presynaptic proteins were quantitatively analyzed under control conditions and after high K+ depolarization in excitatory synapses from dissociated rat hippocampal cultures. Three parallel zones in presynaptic terminals were sampled: zones I and II, each about one synaptic vesicle wide extending from the active zone; and zone III, containing a distal pool of vesicles up to 200 nm from the presynaptic membrane. The distributions of SV2 and synaptophysin, two synaptic vesicle integral membrane proteins, generally followed the distribution of synaptic vesicles, which were typically evenly distributed under control conditions and had a notable depletion in zone III after stimulation. Labels of synapsin I and synuclein, two synaptic vesicle-associated proteins, were similar to each other; both were particularly sparse in zone I under control conditions but showed a prominent enrichment toward the active zone, after stimulation. Labels of Bassoon, Piccolo and RIM 1, three active zone proteins, had very different distribution profiles from one another under control conditions. Bassoon was enriched in zone II, Piccolo and RIM 1 in zone I. After stimulation, Bassoon and Piccolo remained relatively unchanged, but RIM 1 redistributed with a significant decrease in zone I, and increases in zones II and III. These results demonstrate that Bassoon and Piccolo are stable components of the active zone while RIM 1, synapsin I and synuclein undergo dynamic redistribution with synaptic activity.

Animals↗
PubMed1999

Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia.

Metabotropic glutamate receptors (mGluRs) coupled to G-proteins have important roles in the regulation of basal ganglia function. We have examined the localization of the mGluR7 mRNA and mGluR7a protein in the basal ganglia of the rat. Strong mGluR7 hybridization signals are found in cerebral cortex and striatum, but much less intense signals are present in other components of the basal ganglia. Abundant mGluR7a immunoreactivity was found in striatum, globus pallidus (GP), and substantia nigra pars reticulata (SNr). Examination using confocal microscopy together with dendritic and presynaptic markers as well as studies in lesion models provided evidence for the presence of mGluR7a on presynaptic terminals in all three structures. Electron microscopic studies confirmed the presence of mGluR7a in axon terminals in both the striatum and the GP and also revealed the presence of mGluR7a at postsynaptic sites in both of these regions. Our data demonstrate that mGluR7a is located not only on presynaptic glutamatergic terminals of the corticostriatal pathway, where it may serve as an autoreceptor, but also on terminals of striatopallidal and striatonigral projections, where it may modulate the release of gamma-aminobutyric acid (GABA). The presence of mGluR7 at these multiple sites in the basal ganglia suggests that this receptor has a particularly crucial role in modulating neurotransmitter release in major basal ganglia pathways.

Animals↗
PubMed2005

Morphological evidence for GABA/glycine-cocontaining terminals in synaptic contact with neurokinin-1 receptor-expressing neurons in the sacral dorsal commissural nucleus of the rat.

Previous studies have shown that neurons in the sacral dorsal commissural nucleus (SDCN) express neurokinin-1 receptor (NK1R) and can be modulated by the co-release of GABA and glycine (Gly) from single presynaptic terminal. These results raise the possibility that GABA/Gly-cocontaining terminals might make synaptic contacts with NK1R-expressing neurons in the SDCN. In order to provide morphological evidence for this hypothesis, the triple-immunohistochemical studies were performed in the SDCN. Triple-immunofluorescence histochemical study showed that some axon terminals in close association with NK1R-immunopositive (NK1R-ip) neurons in the SDCN were immunopositive for both glutamic acid decarboxylase (GAD) and glycine transporter 2 (GlyT2). In electron microscopic dual- and triple-immunohistochemistry for GAD/GlyT2, GAD/NK1R, GlyT2/NK1R, or GAD/GlyT2/NK1R also revealed dually labeled (GAD/GlyT2-ip) synaptic terminals upon SDCN neurons, as well as GAD- and/or GlyT2-ip axon terminals in synaptic contact with NK1R-ip SDCN neurons. These results suggested that some synaptic terminals upon NK1R-expressing SDCN neurons co-released both GABA and Gly.

Animals↗
PubMed2003

Presynaptic ryanodine-sensitive calcium stores contribute to evoked neurotransmitter release at the basket cell-Purkinje cell synapse.

Presynaptic terminals of cerebellar basket cells are known to contain ryanodine-sensitive calcium stores (RyCSs); recently, it has been shown that these stores control the frequency of miniature synaptic currents in the absence of presynaptic spiking. Here, using paired recordings of basket cell-Purkinje cell synapses, we show that blocking the RyCSs with high concentration of ryanodine decreases the mean amplitude of evoked IPSCs to 70% of the control value. The paired-pulse ratio and failure rate increase, indicating that the reduction stems from a decreased probability of evoked neurotransmitter release. Various control experiments eliminate the possibility of an indirect effect of ryanodine via activation of postsynaptic receptors. Prolonged application of cyclopiazonic acid, a blocker of the endoplasmic reticulum calcium pump, totally abolishes the ryanodine action. Our results indicate that calcium released from presynaptic RyCSs enhances the amplitude of evoked GABAergic synaptic currents. The precise mechanism by which calcium released from internal stores affect action potential-dependent release is unknown; however, our results suggest that these stores do not provide additional calcium for each presynaptic action potential; rather, they appear to enhance depolarization-induced calcium signals indirectly, perhaps by increasing the basal level of cytosolic calcium concentration in the vicinity of release sites.

Animals↗
PubMed1996

Ultrastructural study of synapses in the anterior horn neurons of patients with amyotrophic lateral sclerosis.

This report concerns an ultrastructural examination of the synapses present on the surface of somata of anterior horn neurons of the lumbar spinal cord of seven patients with amyotrophic lateral sclerosis (ALS). Specimens from six age-matched, neurologically normal control individuals were included for comparison. Examination of presynaptic terminals revealed a wide range of changes not only in degenerated neurons (central chromatolytic neurons), but, to a lesser extent, in normal-appearing neurons. The alterations included dense conglomerates of aggregated dark mitochondria and presynaptic vesicles, bundles of neurofilaments, as well as marked increase of presynaptic vesicles. Our observations suggest that in patients with ALS a substantial synaptic alteration does take place in the early stages of anterior horn neuron degeneration and degeneration of axosomatic synapses of anterior horn neurons in ALS may be of consequence on lower motor neuron degeneration.

Aged↗
PubMed2005

Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice.

Major pathological findings in Alzheimer's disease (AD) brain include the deposition of amyloid-beta and synapse loss. Synaptic loss has been shown to correlate with the cognitive decline in AD patients, but the relationship between cerebral amyloidosis and synapse loss is complicated by the presence of neurofibrillary tangles and other lesions in AD brain. With the use of the APP23 transgenic mouse model that overexpresses human amyloid precursor protein (APP) with the Swedish double mutation, we investigated whether the development of cortical amyloid deposition was accompanied by synaptic bouton loss. With stereological methods, we show that despite robust age-related cortical amyloid deposition with associated synaptic degeneration, the total number of cortical synaptophysin-positive presynaptic terminals is not changed in 24-month-old animals compared with 3-, 8-, and 15-month-old APP23 mice. Wild-type mice also do not show an age-related loss of presynaptic boutons in the neocortex and are not significantly different from APP23 mice. Synaptophysin Western blotting revealed no significant difference between APP23 mice and wild-type controls at 3 and 25 months of age. Our results suggest that cerebral amyloidosis is not sufficient to account for the global synapse loss in AD. Alternatively, a putative trophic effect of APP may prevent, compensate, or delay a loss of synapses in this mouse model.

Age Factors↗
PubMed2002

Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats.

Estrogen replacement increases both the number of dendritic spines and the density of axospinous synapses in the hippocampal CA1 region in young rats, yet this is attenuated in aged rats. The estrogen receptor-alpha (ER-alpha) is localized within select spines of CA1 pyramidal cells in young animals and thus may be involved locally in this process. The present study investigated the effects of estrogen on the ultrastructural distribution of ER-alpha in the CA1 of young (3-4 months) and aged (22-23 months) Sprague Dawley rats using postembedding immunogold electron microscopy. Within dendritic spines, most ER-alpha immunoreactivity (IR) was seen in plasmalemmal and cytoplasmic regions of spine heads, with a smaller proportion within 60 nm of the postsynaptic density. In presynaptic terminals, ER-alpha-IR was clustered and often associated with synaptic vesicles. Significant effects of both aging and estrogen were observed. Quantitative analysis revealed that nonsynaptic pools of ER-alpha-IR within the presynaptic and postsynaptic compartments were decreased (35 and 27%, respectively) in the young estrogen-replaced animals compared with those that received vehicle. Such localized regulation of ER-alpha in response to circulating estrogen levels might directly affect synaptic signaling in CA1 pyramidal cells. No estrogen treatment-related differences were observed in the aged animals. However, 50% fewer spines contained ER-alpha in the aged compared with young hippocampus. These data suggest that the decreased responsiveness of hippocampal synapses to estrogen in aged animals may result from age-related decrements in ER-alpha levels and its subcellular localization vis-à-vis the synapse. Such a role for spinous ER-alpha has important implications for age-related attenuation of estrogen-induced hippocampal plasticity.

Age Factors↗