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PubMed1992

SSB, an antigen that selectively labels morphologically distinct synaptic boutons at the Drosophila larval neuromuscular junction.

In this report we describe the expression of Small Synaptic Bouton (SSB), an antigen that is selectively expressed in a specific subset of neuromuscular junction terminals in the body wall of Drosophila larva. The expression of SSB was studied with a polyclonal antibody raised against the cAMP phosphodiesterase of the Drosophila learning mutant dunce (Nighorn et al., 1991, Neuron 6:455-467); however, immunoreactivity was not abolished by the dunce (dnc) alleles dncM14 and dncM11 or deficiencies of the dnc gene, indicating that the antigen labelled could not be the dnc gene product, but another antigen that we termed SSB. Immunoreactivity was localized in the body wall muscles to a specific subset of neuromuscular junction terminals that have been implicated in activity-dependent plasticity. This demonstrates that these morphologically distinct terminals can be immunocytochemically distinguished and that they probably represent innervation by a distinct neuronal population. Confocal and electron microscopic examination demonstrated that staining was restricted to the synaptic boutons themselves, not to neurites or motor axons. Ultrastructural analysis showed label close to synaptic vesicles in the presynaptic terminal and in the surrounding subsynaptic reticulum. Central nervous system (CNS) staining was restricted to a segmentally repeated pattern of cell bodies in the ventral ganglion and to a few small groups of cells in the brain lobes.

Animals↗

PubMed1992

Neuroactive amino acids in organotypic slice cultures of the rat hippocampus: an immunocytochemical study of the distribution of GABA, glutamate, glutamine and taurine.

Antisera raised against protein-glutaraldehyde-amino acid conjugates were used to study the light and electron microscopic distribution of GABA, glutamate, glutamine and taurine in organotypic slice cultures of rat hippocampi. In the stratum oriens and radiatum, glutamate-like immunoreactivity was particularly concentrated in nerve endings establishing asymmetric junctions with dendritic spines. Mossy fiber terminals in CA3 and the dentate hilus were also strongly labeled. A quantitative immunogold analysis of the glutamate-immunolabelled profiles showed a pattern that was highly reminiscent of that previously observed in perfusion-fixed hippocampi, including a correspondingly sparse labeling of glial processes and of presynaptic elements in symmetric synapses. GABA-like immunoreactivity was localized predominantly in interneurons and in presynaptic terminals contacting dendritic shafts and neuronal cell bodies, while immunoreactivities for glutamine and taurine were found mainly in astroglial cells and pyramidal cells, respectively. Our data indicate that the major intrinsic fiber systems of the cultured hippocampi have retained their normal transmitter phenotypes.

Animals↗

PubMed1981

Horizontal cell processes in teleost retina.

Contacts between horizontal and bipolar cells are described in the retina of the teleost Eugerres plumieri. A single, long expansion observed in the external cone horizontal cells makes contact by means of a terminal button with the cell body of a bipolar. It represents the only contact between this class of horizontal cell and the bipolar soma. On the other hand, the medial and internal cone horizontal cells and the rod horizontal cells, which lack such a single, long expansion, display instead numerous short and fine expansions that terminate by means of a terminal knob on a bipolar cell body. The bipolar-destined, short expansions of the rod horizontal cell make contact with large bipolar cell bodies, whereas corresponding short expansions of cone horizontal cells contact small bipolar cell bodies. It is suggested that the ascending horizontal cell process forms presynaptic terminals in the photoreceptor triad complex, and that the single, long and the multiple, short bipolar-destined expansions are postsynaptic to the bipolar cell body.

Animals↗

PubMed1999

LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite.

Structural remodelling of synapses and formation of new synaptic contacts has been postulated as a possible mechanism underlying the late phase of long-term potentiation (LTP), a form of plasticity which is involved in learning and memory. Here we use electron microscopy to analyse the morphology of synapses activated by high-frequency stimulation and identified by accumulated calcium in dendritic spines. LTP induction resulted in a sequence of morphological changes consisting of a transient remodelling of the postsynaptic membrane followed by a marked increase in the proportion of axon terminals contacting two or more dendritic spines. Three-dimensional reconstruction revealed that these spines arose from the same dendrite. As pharmacological blockade of LTP prevented these morphological changes, we conclude that LTP is associated with the formation of new, mature and probably functional synapses contacting the same presynaptic terminal and thereby duplicating activated synapses.

Axons↗

PubMed1980

Inhibition of transmitter release in bullfrog sympathetic ganglia induced by gamma-aminobutyric acid.

1. Effects of gamma-aminobutyric acid (GABA) on the nicotinic synapses in bullfrog sympathetic ganglia were studied. 2. When GABA (100 microM--1 mM) was applied to the ganglion, the post-synaptic membrane depolarized slightly and transiently with a slight decrease in the membrane resistance. 3. GABA (5 microM--1 mM) decreased the amplitude of the fast excitatory post-synaptic potentials (fast e.p.s.p.) and its quantal content without a significant change in the quantal size, and these effects were seen even after the subsidence of the membrane depolarization. Picrotoxin (10 microM) did not antagonize the GABA action. 4. The sensitivity of the subsynaptic membrane to ACh was unaffected by GABA. On the other hand, the synaptic current underlying the fast e.p.s.p. was significantly depressed in the presence of GABA. 5. Neither the frequency nor the amplitude of the miniature e.p.s.p.s which occurred spontaneously were altered by GABA, in either normal or high K+ solutions. 6. The depressant action of GABA on the fast e.p.s.p. was not changed in a high K+ solution, while it was markedly decreased in a Cl- -deficient solution. 7. A small, but significant reduction in the amplitude of the presynaptic terminal spike recorded with a focal extracellular electrode was observed under the effect of GABA. 8. It was concluded that GABA inhibits synaptic transmission of bullfrog sympathetic ganglion mainly by decreasing the evoked release of transmitter and only partly by post-synpatic action. Possible mechanisms of the presynaptic action of GABA were discussed.

Acetylcholine↗

PubMed2004

Stressor-related impairment of synaptic transmission in hippocampal slices from alpha-synuclein knockout mice.

The role of alpha-synuclein (alpha-Syn) has recently received considerable attention because it seems to play a role in Parkinson's disease (PD). Missense mutations in the alpha-Syn gene were found in autosomal dominant PD and alpha-Syn was shown to be a major constituent of protein aggregates in sporadic PD and other synucleinopathies. Under normal conditions, alpha-Syn protein is found exclusively in synaptic terminals. However, the potential participation of alpha-synuclein in maintaining and regulating synaptic efficacy is unknown. We have investigated the excitatory synaptic modulation of alpha-synuclein in CA1 pyramidal neurons, using the in vitro hippocampal slice technique. The 4-aminopyridine-induced increase of both spontaneous excitatory postsynaptic current (EPSC) frequency and amplitude was significantly higher in alpha-Syn wild-type than knockout mice, whereas basal spontaneous EPSC frequency and amplitude was similar in both animals. As the spontaneous synaptic activity was abolished by tetrodotoxin, which indicates that it was a result of action potential-mediated transmitter release from presynaptic terminals, spontaneous EPSC changes observed in alpha-Syn knockout mice suggest that these animals present a modification of synaptic transmission with a presynaptic origin. Presynaptic depression of evoked EPSCs by hypoxia or adenosine was significantly larger in alpha-Syn knockout than in wild-type mice, further supporting the hypothesis of regulation of synaptic transmission by alpha-Syn. Together, these observations indicate that the loss of alpha-Syn reduces synaptic efficacy when the probability of transmitter release is modified. We conclude that alpha-Syn might have important actions on the maintenance of the functional integrity of synaptic transmission and its regulation in hippocampus.

4-Aminopyridine↗

PubMed1982

Presynaptic effects of sodium bisulfite at the frog neuromuscular junction.

Both spontaneous and evoked transmitter release from the frog neuromuscular junction can be modified by application of sodium bisulfite, a reagent specific for disulfide bonds. An increase in miniature endplate frequency is produced that is not dependent on external calcium, sodium, or presynaptic terminal depolarization. The increased release can be halted by application of the sulfhydryl oxidizing agent DTNB. The response of bisulfite can be prevented by prior treatment of the endplate with acetylcholine or an anticholinesterase. It is concluded that bisulfite produces its effects by acting on a protein in the presynaptic membrane that is involved in regulation of transmitter release.

Acetylcholine↗

PubMed1994

Alpha-, beta II- and gamma-subspecies of protein kinase C localized in the monkey hippocampus: pre- and post-synaptic localization of gamma-subspecies.

Protein kinase C (PKC) has attracted wide attention as a key enzyme for the expression of long-term potentiation in the hippocampus, a basic model for memory. It is of interest to study the detailed localization of PKC subspecies in the monkey hippocampus. We used immunocytochemistry to examine the localization of PKC subspecies in the hippocampus of the monkey, Macaca mulatta. Subspecies of PKC in the monkey could be separated by hydroxyapatite chromatography and the elution profile proved to be similar to that of the rat. Antibodies against each alpha, beta II and gamma-subspecies of the rat specifically reacted with the respective subspecies of monkey PKC. The alpha-, beta II- and gamma-subspecies were distinctly distributed in the hippocampus. The beta I-subspecies was not evident in the hippocampus. While both the alpha- and gamma-subspecies immunoreactive pyramidal cells were distributed throughout the hippocampus (CA1-CA3), the beta II-subspecies immunoreactive cells were scattered only in the CA1 region. The gamma-subspecies was found in granule cells and dendrites in the dentate gyrus, in mossy fibers and in their terminals in the CA3 region. The alpha-subspecies was also present in granule cells and in the dendrites but not in the mossy fibers. Glial cells did not stain with any of the antibodies used. Electron microscopy clearly showed that the gamma-subspecies was localized in both presynaptic terminals and post-synaptic dendrites. These observations suggest that subspecies of PKC in the monkey hippocampus may be involved in distinct functions and that the gamma-subspecies of PKC may act pre- and post-synaptically in pyramidal cells of the hippocampus.

Amino Acid Sequence↗

PubMed2001

How does calcium trigger neurotransmitter release?

Recent work has established that different geometric arrangements of calcium channels are found at different presynaptic terminals, leading to a wide spectrum of calcium signals for triggering neurotransmitter release. These calcium signals are apparently transduced by synaptotagmins - calcium-binding proteins found in synaptic vesicles. New biochemical results indicate that all synaptotagmins undergo calcium-dependent interactions with membrane lipids and a number of other presynaptic proteins, but which of these interactions is responsible for calcium-triggered transmitter release remains unclear.

Animals↗

PubMed1993

Ontogeny of synaptophysin and synaptoporin in the central nervous system: differential expression in striatal neurons and their afferents during development.

The expression of the synaptic vesicle antigens synaptophysin (SY) and synaptoporin (SO) was studied in the rat striatum, which contains a nearly homogeneous population of GABAergic neurons. In situ hybridization revealed high levels of SY transcripts in the striatal anlage from embryonic day (E) 14 until birth. In contrast, SO hydridization signals were low, and no immunoreactive cell bodies were detected at these stages of development. At E 14, SY-immunoreactivity was restricted to perikarya. In later prenatal stages of development SY-immunoreactivity appeared in puncta (identified as terminals containing immunostained synaptic vesicles), fibers, thick fiber bundles and 'patches'. In postnatal and adult animals, perikarya of striatal neurons exhibited immunoreaction for SO; ultrastructurally SO antigen was found in the Golgi apparatus and in multivesicular bodies. SO-positive boutons were rare in the striatum. In the neuropil, numerous presynaptic terminals positive for SY were observed. Our data indicate that the expression of synaptic vesicle proteins in GABAergic neurons of the striatum is developmentally regulated. Whereas SY is prevalent during embryonic development, SO is the major synaptic vesicle antigen expressed postnatally by striatal neurons which project to the globus pallidus and the substantia nigra. In contrast synapses of striatal afferents (predominantly from cortex, thalamus and substantia nigra) contain SY.

Animals↗

PubMed1989

Presence of calcium/calmodulin-dependent protein kinase II in nerve terminals of rat brain.

Calcium/calmodulin-dependent protein kinase type II, a multimeric 550-650 kilodalton enzyme composed of major alpha (50 kilodalton) and beta/beta' (60/58 kilodalton) subunits, is present in high concentrations in mammalian brain. Previous immunocytochemical studies indicated that the enzyme is enriched in cell bodies and dendrites, but did not show a clear-cut localization in nerve terminals. The present study presents evidence, using lesion-induced degenerations of pre- and postsynaptic neuronal populations in the neostriatum and substantia nigra, that calcium/calmodulin-dependent protein kinase II, as measured both by autophosphorylation of enzyme subunits and by synapsin I kinase activity, is present in high concentrations in several populations of presynaptic terminals. Lesions of the corticostriatal tract decreased the amount of enzyme by 30-40% in the neostriatum, a decrease similar to that seen in the same region of synapsin I, a general nerve terminal marker. Lesions of the striatonigral tract induced an even more pronounced decrease of the enzyme in the substantia nigra; this decrease was larger than the lesion-induced change of synapsin I seen in the same region. Our data therefore indicate that certain nerve terminal populations in the rat brain contain high levels of calcium/calmodulin-dependent protein kinase II.

Animals↗

PubMed2002

The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic.

JANUS, THE ANCIENT ROMAN GOD OF GATES AND DOORS HAD TWO FACES: one looked into the past, and the other, into the future. Do neurons possess a Janus face when it comes to neurotransmitters, or a given neuron is to be forever solely gamma-aminobutyric acid (GABA) ergic, glutamatergic, dopaminergic, peptidergic, or YOURPREFERREDTRANSMITTERergic? The answer is that the terminals of many neurons are homes to even more than two neurotransmitters. All this in spite of the "one neuron-one transmitter" usual misinterpretation of Sir Henry Hallett Dale's postulate, originally meant to indicate that a metabolic process taking place in the cell body can influence all processes of the same neuron. A large variety of neurons in the CNS, many of them GABAergic, produce and release chemicals that satisfy some of the criteria used to define neurotransmitters. The usual scenario for a dual-transmitter terminal is that the fast-acting transmitter such as GABA or glutamate is stored in regular synaptic vesicles, whereas a neuropeptide is stored in dense core vesicles (1). The vesicular zinc found in many glutamatergic terminals also may be considered to be a second neurotransmitter, based on its vesicular packaging with the aid of a specific vesicular transporter, and its postsynaptic actions through high-affinity binding sites and permeation through certain channels (2). Whenever a "fast" and a "slow" neurotransmitter are present in the same presynaptic terminal, it is customary to assume that their release can be differentially regulated (1). There is little convincing experimental support for this phenomenon in the mammalian CNS. The coexistence of two "fast" neurotransmitters in the same terminal is less frequent, but not unheard of. In neonatal sympathetic neurons cocultured with cardiac myocytes, norepinephrine and acetylcholine coexist and have opposite actions on the cardiac muscle cells (3). Very recently we learned that brain-derived neurotrophic factor acting at the low-affinity neurotrophin receptor p75(NTR), perhaps as part of a programmed developmental switch, can convert the phenotype of the sympathetic neuron from noradrenergic to cholinergic (4). Other examples of two fast neurotransmitters released from the same neuron include GABA and glycine in interneurons of the spinal cord (5) and glutamate and dopamine in ventral midbrain dopamine neurons (6). Of all CNS neurons, the granule cells of the dentate gyrus appear to be the champions of neurotransmitter colocalization: glutamate, enkephalin, dynorphin, zinc, and finally GABA (2)(7)(8)(9). With this many transmitters in a single neuron, there are probably different ways in which they can be released. Dynorphin and other opioid peptides can be released directly from the dendrites to inhibit excitatory transmission (8). A similar mechanism may take place for GABA, as described in cortical GABAergic neurons (10).

Journal Article↗

PubMed1976

The facial motor nucleus of the opossum: synaptic endings on dendrites.

The diameters of dendrites of large, medium and small neurons (Falls and King, '76) were measured from Golgi impregnations of the opossum facial motor nucleus in order to classify dendritic profiles sectioned in the transverse plane in electron micrographs. Three categories of dendrites are described: (1) proximal (4-7 mu in diameter); (2) intermediate (2-4 mu in diameter) and (3) distal (0.5-2 mu in diameter). The distribution of axodendritic synaptic endings was determined, recognizing that the neuronal source of individual dendritic profiles when seen in the transverse plane of section cannot be absolutely determined in view of the overlap in size of the dendrites issuing from the three types of neurons. Presynaptic terminals were categorized according to vesicle shape (spherical, pleomorphic or ellipsoidal), vesicle size, terminal size, junctional characteristics and post synaptic distribution. The vesicle size is expressed as a mean area (nm2) and was determined by using a cybergraphic tablet and a PDP-12 computer system. In any given plane of section, synaptic terminals cover most of the membrane of proximal dendrites and decrease in number as intermediate and distal dendrites are encountered. In Golgi impregnations four classes of afferent fibers which ramify among the dendrites of facial neurons can be distinguished. As yet, their sources have not been identified. Possible sites of origin for presynaptic profiles are discussed in the context of previous light microscopic findings.

Animals↗

PubMed2005

Lysosomal pathology associated with alpha-synuclein accumulation in transgenic models using an eGFP fusion protein.

Disorders with Lewy body (LB) formation, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein accumulation in the neuronal cell body. Recent studies have suggested that in addition to LBs, alpha-synuclein might accumulate more widely throughout the neurons and their processes, leading to neurodegeneration and functional impairment. The precise patterns of alpha-synuclein accumulation in vivo, however, and its relationship with subcellular neuronal alterations such as lysosomal pathology are not completely clear. To this end, we developed transgenic (tg) in vivo and in vitro models expressing a stable enhanced green fluorescent protein (eGFP) tagged in the C-terminal site of a human (h)alpha-synuclein construct under the regulatory control of the platelet-derived growth factor-beta (PDGFbeta) promoter and carried out confocal, ultrastructural, and biochemical studies. In tg mice, confocal studies demonstrated a wide distribution of halpha-synuclein-eGFP in the neuronal cell bodies, axons, and presynaptic terminals. In several neuronal cell bodies and their neurites, halpha-synuclein-eGFP was found not only as inclusions but also as discrete granular structures that in double-labeling studies colocalized with antibodies against halpha-synuclein and the lysosomal marker cathepsin D. Consistent with these findings, ultrastructural analysis showed that halpha-synuclein-eGFP overexpression resulted in the accumulation of electrodense inclusions and laminated bodies suggestive of lysosomal pathology, and that the halpha-synuclein-eGFP protein was more abundant in the lysosomal fractions of the tg animals. Taken together, these findings support the notion that enhanced visualization of alpha-synuclein utilizing a hybrid eGFP molecule reveals a more widespread accumulation of this molecule in several neuronal compartments, promoting lysosomal dysfunction. Furthermore, the PDGFbeta-halpha-synuclein-eGFP tg model might be a valuable tool in testing new treatments for LBD in a fast and reliable manner.

Animals↗

PubMedDate not supplied

Presynaptic beta-adrenoceptors.

The existence of facilitatory presynaptic beta-adrenoceptors has been shown in approximately 30 tissues of 6 different species including human. A positive feed back loop for further release of the transmitter appears to be activated by an endogenous agonist, epinephrine, taken up and released as a cotransmitter with norepinephrine rather than norepinephrine itself released from peripheral noradrenergic nerve terminals. Presynaptic beta-adrenoceptors are mainly of a beta 2-subtype. Some beta 1-subtype receptors are also suggested. There coexist presynaptic beta 1- and beta 2-adrenoceptors in cat and rat hypothalamus. Higher sensitivity of peripheral presynaptic beta-adrenoceptors to isoproterenol may be implicated in the early development of hypertension in SHR. Epinephrine taken up and released initiates the development of hypertension in rats via activation of these receptors. Increased activation of these receptors by epinephrine may play a role in the development of essential hypertension. The antihypertensive action of beta-antagonists may be in part due to blockade of these facilitatory presynaptic beta-adrenoceptors.

Adrenergic beta-Antagonists↗

PubMed1978

Observations on the commissural projection to the dentate gyrus in the Reeler mutant mouse.

The commissural projection to the displaced granule cells of the dentate gyrus in Reeler mutant mice has been examined with autoradiography, and light and electron microscopy. Commissural terminals in Reeler are confined to the hilar region, in contrast to normal littermates in which this projection is restricted to the inner part of the molecular layer. Granule cell somata in Reeler, but only exceptionally in normal littermates, are invested with spines, which have postsynaptic specializations, but no spine apparatus, and are contacted by presynaptic terminals. Between 20 and 30 h after destruction of the commissural fibres in Reeler, degenerating terminals can be found contacting both somatic and dendritic spines in the hilus; 30 h after decommissuration the number and length of spines on the somata and proximal dendrites of Golgi impregnated cells is greatly reduced, while spines on the distal parts of the dendritic tree are unaffected. A similar pattern of degeneration after decomissuration is found in the inner molecular layer of normal littermates. These results are discussed in terms of factors controlling the normal development of afferent projections. The paper concludes with an analysis of a potential methodological hazard. A change in mean spine length will of itself result in a change in the number of visible spines in golgi material. A quantitative assessment of the relation between spine length and the number of visible spines is developed for spherical cell bodies and cylindrical dendrites.

Animals↗

PubMed2002

Reduction of neurotransmitter release by the exogenous H3 domain peptide of HPC-1/syntaxin 1A in cultured rat hippocampal neurons.

The membrane protein HPC-1/syntaxin 1A plays a key role in synaptic vesicle exocytosis in the presynaptic terminal. In particular, the H3 domain of HPC-1/syntaxin 1A participates in several protein-protein interactions that regulate neurotransmitter release. To investigate H3 domain function in neurotransmitter release, we used paired whole-cell patch clamping to record the evoked inhibitory postsynaptic currents in cultured hippocampal neurons. Introducing H3 domain peptide into the presynaptic neuron with a patch electrode depressed neurotransmitter release in a stimulation-frequency-dependent manner. Recovery from synaptic vesicle depletion induced by tetanic stimulation was significantly slowed by exogenous H3 domain peptide. These results suggest that the H3 domain peptide reduces neurotransmitter release by retarding the refilling of readily releasable vesicles.

Animals↗

PubMed2006

Role of efficient neurotransmitter release in barrel map development.

Cortical maps are remarkably precise, with organized arrays of thalamocortical afferents (TCAs) that project into distinct neuronal modules. Here, we present evidence for the involvement of efficient neurotransmitter release in mouse cortical barrel map development using barrelless mice, a loss-of-function mutant of calcium/calmodulin-activated adenylyl cyclase I (AC1), and mice with a mutation in Rab3-interacting molecule 1alpha (RIM1alpha), an active zone protein that regulates neurotransmitter release. We demonstrate that release efficacy is substantially decreased in barrelless TCAs. We identify RIMs as important phosphorylation targets for AC1 in the presynaptic terminal. We further show that RIM1alpha mutant mice have reduced TCA neurotransmitter release efficacy and barrel map deficits, although not as severe as those found in barrelless mice. This supports the role of RIM proteins in mediating, in part, AC1 signaling in barrel map development. Finally, we present a model to show how inadequacies in presynaptic function can interfere with activity-dependent processes in neuronal circuit formation. These results demonstrate how efficient synaptic transmission mediated by AC1 function contributes to the development of cortical barrel maps.

Adenylyl Cyclases↗