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PubMed2003

Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition.

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.

Action Potentials↗
PubMed1974

Synaptic vesicle depletion and recovery in cat sympathetic ganglia electrically stimulated in vivo. Evidence for transmitter secretion by exocytosis.

This study examined the ultrastructure of presynaptic terminals after short periods of vigorous acetylcholine (ACh) secretion in the cat superior cervical ganglion in vivo. Experimental trunks of cats anesthetized with chloralose-urethane were stimulated supra-maximally for periods of 15-30 min and at several frequencies including the upper physiological range (5-10 Hz). Stimulated and contralateral control ganglia from each animal were fixed by intra-arterial aldehyde perfusion, processed simultaneously, and compared by electron microscopy. Stimulation produced an absolute decrease in the number of synaptic vesicles, an enlargement of axonal surface membrane, and distinct alterations in the shape of presynaptic terminals. Virtually complete recovery occurred within 1 h after stimulation at 10 Hz for 30 min. These results support the hypothesis that ACh release at mammalian axodendritic synapses occurs by exocytosis of synaptic vesicles resulting in the incorporation of vesicle membrane into the presynaptic membrane and that synaptic vesicles subsequently are reformed from plasma membrane.

Acetylcholine↗
PubMed1996

Synaptophysin in spinal anterior horn in aging and ALS: an immunohistological study.

Aged-related spinal cord changes such as neuronal loss have been related to the degree of clinical severity of amyotrophic lateral sclerosis (ALS); morphological data on synapses are, however, wanting. Variations in synaptophysin (Sph) expression in aging and ALS were thus studied at the level of lower motor neurons in 40 controls with non-neurological diseases and 11 cases of ALS. Control sections of formalin fixed paraffin embedded cervical (C7/8), thoracic (T10) and lumbar spinal cord (L5) and C6, C7, C8 and L5 of ALS cases were stained with haematoxylin and eosin, luxol fast blue (LFB), and immunostained with a mouse monoclonal antibody against Sph. The neuropil of the anterior horn (AH) in all control cases demonstrated Sph positivity. A dot-like pattern of positivity of presynaptic terminals on soma of motor neurons and fine immunoreactivity along neuronal processes were observed. A significant reduction of Sph immunostaining was observed in the neuropil with increasing age and 3 different somatic patterns were seen: a- well preserved Sph reactivity around the soma and the proximal dendrites of histologically normal neurons; b- few chromatolytic neurons showing large numbers of dot-like presynaptic terminals around the cell body and in a "fused" pattern; c- intense, diffuse, and homogeneous reactivity of some neurons. Attenuation of Sph reactivity in the AH neuropil, to its complete loss, was observed in all ALS cases. In addition to patterns a-c, two additional microscopic findings were noted in ALS: d- chromatolytic neurons showing complete absence of Sph reactivity; e- absence of Sph reactivity around the soma and the proximal dendrites of histologically normal surviving neurons. Our findings demonstrate that there is a decrease in Sph immunostaining with aging, thus suggesting an alteration in dendritic networks of the AH with aging. Changes in the pattern of Sph immunoreactivity in cell bodies may represent synaptic plasticity and/or degeneration. Reinnervation may also be a possible mechanism as a response to neuronal loss in oldest control cases. Sph reactivity results may thus lend support to the presence of superimposed aging components in ALS cases which may give an insight into explaining the increasing severity of the disease which is encountered with advancing age.

Adult↗
PubMed1990

Effects of synapsin I and calcium/calmodulin-dependent protein kinase II on spontaneous neurotransmitter release in the squid giant synapse.

The molecular events that control synaptic vesicle availability in chemical synaptic junctions have not been fully clarified. Among the protein molecules specifically located in presynaptic terminals, synapsin I and calcium/calmodulin-dependent protein kinase II (CaM kinase II) have been shown to modulate evoked transmitter release in the squid giant synapse. In the present study, analysis of synaptic noise in this chemical junction was used to determine whether these proteins also play a role in the control of spontaneous and enhanced spontaneous transmitter release. Injections of dephosphorylated synapsin I into the presynaptic terminal reduced the rate of spontaneous and enhanced quantal release, whereas injection of phosphorylated synapsin I did not modify such release. By contrast CaM kinase II injection increased enhanced miniature release without affecting spontaneous miniature frequency. These results support the view that dephosphorylated synapsin I "cages" synaptic vesicles while CaM kinase II, by phosphorylating synapsin I, "decages" these organelles and increases their availability for release without affecting the release mechanism itself.

Animals↗
PubMed2006

BCL-xL regulates synaptic plasticity.

Mitochondria are the predominant organelle within many presynaptic terminals. During times of high synaptic activity, they affect intracellular calcium homeostasis and provide the energy needed for synaptic vesicle recycling and for the continued operation of membrane ion pumps. Recent discoveries have altered our ideas about the role of mitochondria in the synapse. Mitochondrial localization, morphology, and docking at synaptic sites may indeed alter the kinetics of transmitter release and calcium homeostasis in the presynaptic terminal. In addition, the mitochondrial ion channel BCL-xL, known as a protector against programmed cell death, regulates mitochondrial membrane conductance and bioenergetics in the synapse and can thereby alter synaptic transmitter release and the recycling of pools of synaptic vesicles. BCL-xL, therefore, not only affects the life and death of the cell soma, but its actions in the synapse may underlie the regulation of basic synaptic processes that subtend learning, memory and synaptic development.

Animals↗
PubMed1998

Endogenous NMDA-receptor activation regulates glutamate release in cultured spinal neurons.

N-methyl--aspartate (NMDA) receptor activation plays a fundamental role in the genesis of electrical activity of immature neurons and may participate in activity-dependent aspects of CNS development. A recent study has suggested that NMDA-receptor-mediated glutamatergic neurotransmission might occur in the developing spinal cord via activation of nonsynaptic receptors, but the details of NMDA-receptor activation in the developing CNS are not yet well understood. We describe here a model of cultured spinal neurons that display ongoing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity characterized by spontaneous excitatory postsynaptic currents (EPSCs), with NMDA-receptor activity detectable only as single channel events. -2-amino-5-phosphonovaleric acid (100 microM) and tetrodotoxin (TTX) 100 nM each reduced the occurrence of spontaneous AMPA EPSCs; quantal analysis showed a decrease in the number of released quanta but no changes in quantal size, indicating that NMDA-receptor activation and Na+ channel activity affect the generation of spontaneous AMPA EPSCs, at least in part, via mechanisms that impinge on the presynaptic terminal. Once the Mg2+-block was released, activity of NMDA receptors dramatically increased the release of quantal and multiquantal amounts of glutamate, indicating that the NMDA receptors are physiologically coupled to glutamate release. In Mg2+-free solution, TTX application elicited an increase in the number of quantal AMPA EPSCs and a reduction in the number of multiquantal EPSCs, consistent with an effect of NMDA-receptor activation on presynaptic terminals. Our results suggest that endogenous activity at a small number of NMDA receptors can regulate the release of neurotransmitters at developing AMPA synapses.

2-Amino-5-phosphonovalerate↗
PubMed1968

The fine structure of puromycin-induced changes in mouse entorhinal cortex.

Bitemporal intracerebral injections of puromycin in mice suppress indefinitely expression of memory of avoidance-discrimination learning. Ultrastructural studies of the entorhinal cortex of puromycin-treated mice revealed the following: (a) Abnormalities were not observed in presynaptic terminals and synaptic clefts; many postsynaptic dendrites or somas contained swollen mitochondria. (b) Dispersion of polyribosomes into single units or condensation of ribosomes into irregular aggregates with loss of "distinctiveness" was noted in a few neurons 7-27 hr after puromycin treatment. (c) Cytoplasmic aggregates of granular or amorphous material were frequently noted within otherwise normal neuronal perikarya. (d) Mitochondria in many neuronal perikarya and dendrites were swollen. Mitochondria in axons, presynaptic terminals, and glial cells were unaltered. The relationships between these lesions and the effect of puromycin on protein synthesis and memory are examined. It is suggested that the disaggregation of polysomes is too limited to explain the effect of puromycin on memory. Special emphasis is given to the swelling of mitochondria. The possible mechanisms and the significance of this lesion are discussed.

Animals↗
PubMed1987

A serial-section study of perforated synapses in rat neocortex.

The morphology of perforated synapses in the molecular layer of rat parietal cortex has been studied in 28-day-old animals. Of the perforated synapses analyzed, 92% were axospinous and of these all had asymmetrical contacts. A spinule was present in 20% of them, and 63% had a negative curvature (concave with respect to the presynaptic terminal) overall. Up to 95% of perforated synapses had one or more negatively-curved segments. The perforated synapses studied were characterized by postsynaptic densities (PSD) with a mean length of 581 nm, compared with 233 nm for non-perforated synapses. A study of over 100 serially sectioned synapses demonstrated that, in perforated synapses, the PSD and perforations often had a highly irregular shape and arrangement, the site of the perforation frequently projected into the presynaptic terminal, and coated evaginations of membrane, or coated vesicles, were sometimes found at the site of a perforation or towards the periphery of perforated PSDs. Preliminary reconstructions of perforated synapses suggest that, for descriptive purposes, three types can be recognized. Criteria are formulated for determining, on the basis of a study of single sections, which non-perforated profiles belong to perforated synapses.

Animals↗
PubMed2004

Nervous wreck, an SH3 adaptor protein that interacts with Wsp, regulates synaptic growth in Drosophila.

We describe the isolation and characterization of nwk (nervous wreck), a temperature-sensitive paralytic mutant that causes excessive growth of larval neuromuscular junctions (NMJs), resulting in increased synaptic bouton number and branch formation. Ultrastructurally, mutant boutons have reduced size and fewer active zones, associated with a reduction in synaptic transmission. nwk encodes an FCH and SH3 domain-containing adaptor protein that localizes to the periactive zone of presynaptic terminals and binds to the Drosophila ortholog of Wasp (Wsp), a key regulator of actin polymerization. wsp null mutants display synaptic overgrowth similar to nwk and enhance the nwk morphological phenotype in a dose-dependent manner. Evolutionarily, Nwk belongs to a previously undescribed family of adaptor proteins that includes the human srGAPs, which regulate Rho activity downstream of Robo receptors. We propose that Nwk controls synapse morphology by regulating actin dynamics downstream of growth signals in presynaptic terminals.

Adaptor Proteins, Vesicular Transport↗
PubMed1990

Visualization of differential neurofilament phosphorylation in the pre- and postsynaptic axoplasm of the squid giant synapse: an electron spectroscopic study.

When inelastically scattered electrons with an energy loss specific for interaction with phosphorus atoms were used for visualization of sections of squid axons, bead-like domains of elongated proteins, presumably neurofilaments, exhibited distinct phosphorus signals. A marked asymmetry of these phosphorus signals was detectable between the pre- and the postsynaptic cytoskeleton of the giant synapse. Signals were very numerous and intense in the presynaptic terminal, while rare and weak in the postsynaptic axoplasm. The giant axon revealed a delayed appearance of phosphorus signals in its course from the cell bodies in the giant fibre lobe to its exit from the stellate ganglion. Numerous and intense phosphorylation signals were evident only in the peripheral giant axon. Asymmetry in the distribution of phosphorus signals between pre- and postsynaptic axoplasm paralleled differences in Ca(2+)-buffering mechanisms, as shown in a previous study. In the presynaptic terminal patterns of phosphorus signals correlated with precipitates which had formed after intra-axonal injection of calcium. Our observations suggest a role of phosphorylated neurofilaments in binding of calcium in the squid synapse.

Animals↗
PubMed2002

[Calcium channel subtypes mediating central synaptic transmission].

It is well established that neurotransmitter release is triggered by Ca2+ entry into the presynaptic terminals through voltage-dependent Ca2+ channels. In the mammalian central nervous system, multiple types of Ca2+ channels including N-type, P/Q-type and other types mediate fast synaptic transmission. Electrophysiological studies using type-specific antagonists for Ca2+ channels have estimated the relative contribution of N-, P/Q- and other types of Ca2+ channels in excitatory and inhibitory synaptic transmission in the hippocampus, cerebellum, spinal cord, brain stem, and striatum. A recent study has demonstrated that activation of presynaptic dopamine D2-like receptors selectively block N-type Ca2+ channels to reduce GABA release onto cholinergic interneurons in the rat striatum. In addition, it has been recently clarified that the contribution of N-type Ca2+ channels to synaptic transmission is restricted to the early postnatal period at synapses in auditory brain stem, cerebellum, or thalamus. Advanced morphological studies are necessary for the further understanding of the subcellular localization of each subtype of Ca2+ channels and receptors modulating the transmitter release through Ca2+ channel activity in relation to the release sites in the presynaptic terminals.

Animals↗
PubMed1993

A common rule governs the synaptic locus of both short-term and long-term potentiation.

BACKGROUND: At synapses between neurons in the brain, transmitter molecules are released from presynaptic terminals in multi-molecular packets called quanta. Excitatory synapses in the CA1 region of the hippocampus show a long-lasting increase in strength known as long-term potentiation (LTP), which may be important for some kinds of learning and memory. LTP can involve an increase in the number of quanta released, or in the size of the response each quantum produces in the postsynaptic cell, or both, depending on the initial condition of the synapse. These synapses also show two forms of brief potentiation: post-tetanic potentiation (PTP), which lasts for a minute or less and involves only modifications at the presynaptic terminal, and short-term potentiation (STP), which lasts rather longer. The significance of STP, the mechanisms whereby it is produced and its relationship to other forms of potentiation are poorly understood. We have studied STP electrophysiologically using slices of the rat hippocampus maintained in vitro. RESULTS: We found that STP, like LTP, can involve increases in either the number of quanta released, or their postsynaptic effect, or both. The rule governing the relative contribution from these two mechanisms appears to be the same as operates during LTP. Both the presynaptic and postsynaptic changes can develop equally rapidly and so must involve fast-acting messenger systems. CONCLUSIONS: STP seems to be a separate phenomenon from PTP, but appears closely related to LTP. The rapidity of its onset may require a reappraisal of current understanding of the messenger systems involved in bringing about changes in synaptic strength.

Journal Article↗
PubMed1987

Ultrastructural effects of monocular deprivation in the neuropil of nucleus rotundus in the zebra finch: a quantitative electron microscopic study.

Ultrastructural effects of monocular deprivation starting at hatching have been studied in the neuropil of nucleus rotundus, the thalamic visual relay station of the tectofugal pathway in birds. Synaptic density, presynaptic terminal size, and length of postsynaptic density (PSD) have been quantified in juvenile (20-day) and adult (100-day) zebra finches. These parameters are mature in 20-day-old zebra finches when reared under normal conditions. Alterations obtained by monocular deprivation were: The synaptic density increases by 35% in the nucleus rotundus of both sides of the brain above normal values in juvenile birds. In adult birds only the deprived side maintains this hypertrophy of synaptic density (33%), the non-deprived side returns to normal values. The presynaptic terminal size remains small in the deprived nucleus of 20-day- and 100-day-old animals, whereas the non-deprived nucleus is not affected. By the age of 20 days the length of PSD in deprived and non-deprived nuclei is not reduced as much as in normally reared zebra finches. By the age of 100 days, however, the PSDs of both sides of monocularly deprived birds show a further reduction of their median length and do not differ from PSDs of zebra finches reared under normal conditions.

Age Factors↗
PubMed1985

Differential rearing effects on rat visual cortex synapses. II. Synaptic morphometry.

An array of morphological measurements was made upon spine synapses in the upper 4 layers of occipital cortex of rats reared for 30 days after weaning in complex (EC), social (SC) or isolated (IC) environments. The mean length of the synaptic contact zone (post-synaptic density plus interpolated non-impregnated regions) was greater in layer IV of EC rats than in IC rats. SC rats were intermediate, not differing from other groups. There were no differences in these measures in other layers, nor were there differences in the mean area or perimeter of presynaptic terminals or postsynaptic processes, the relative frequency of headed vs sessile shaped spines, the length of the apposition between pre- and postsynaptic processes, or the ratio of perimeter to area (inverse roundness) of postsynaptic processes. Cleft width was greater in regions of the contact zone where postsynaptic density was present than in regions where it was absent (perforations), but, aside from the previously described differences in the frequency of perforated synapses, there were no group differences in cleft width. The maximum length of synaptic contact zones and the maximum area of presynaptic terminals was greater in EC than in IC rats in layer IV, but not in other layers, with SC rats again intermediate. These results support previous findings of larger layer IV synaptic contacts in EC rats and suggest that the size of some synaptic components can change without changes in others, a population of very large synapses is seen in layer IV of EC rats that is not seen in IC rats, and perforations may be unlikely sites of synapse splitting, given that membranes are more closely apposed in these regions, rather than pulling apart.

Animals↗
PubMed1999

Myosin Va movements in normal and dilute-lethal axons provide support for a dual filament motor complex.

To investigate the role that myosin Va plays in axonal transport of organelles, myosin Va-associated organelle movements were monitored in living neurons using microinjected fluorescently labeled antibodies to myosin Va or expression of a green fluorescent protein-myosin Va tail construct. Myosin Va-associated organelles made rapid bi-directional movements in both normal and dilute-lethal (myosin Va null) neurites. In normal neurons, depolymerization of microtubules by nocodazole slowed, but did not stop movement. In contrast, depolymerization of microtubules in dilute-lethal neurons stopped movement. Myosin Va or synaptic vesicle protein 2 (SV2), which partially colocalizes with myosin Va on organelles, did not accumulate in dilute-lethal neuronal cell bodies because of an anterograde bias associated with organelle transport. However, SV2 showed peripheral accumulations in axon regions of dilute-lethal neurons rich in tyrosinated tubulin. This suggests that myosin Va-associated organelles become stranded in regions rich in dynamic microtubule endings. Consistent with these observations, presynaptic terminals of cerebellar granule cells in dilute-lethal mice showed increased cross-sectional area, and had greater numbers of both synaptic and larger SV2 positive vesicles. Together, these results indicate that myosin Va binds to organelles that are transported in axons along microtubules. This is consistent with both actin- and microtubule-based motors being present on these organelles. Although myosin V activity is not necessary for long-range transport in axons, myosin Va activity is necessary for local movement or processing of organelles in regions, such as presynaptic terminals that lack microtubules.

Actin Cytoskeleton↗
PubMed1995

Expression and regulation of brain metallothionein.

Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These "vesicular" pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guillaine-Barré syndrome, hepatic encephalopathy, multiple sclerosis, Parkinson's disease, Pick's disease, retinitis pigmentosa, retinal dystrophy, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT isoforms and other low molecular weight zinc-binding proteins in these conditions, diseases, disorders, or syndromes is being delineated at this time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytokine-induced induction of MT provides a long-lasting protection to avert oxidative damage.

Amino Acids↗
PubMed2002

Modulation of synaptic transmission by oxytocin and vasopressin in the supraoptic nucleus.

It is now generally accepted that magnocellular neurons of the supraoptic and paraventricular nuclei release the neuropeptides oxytocin and vasopressin from their dendrites. Peptide release from their axon terminals in the posterior pituitary and dendrites differ in dynamics suggesting that they may be independently regulated. The dendritic release of peptide within the supraoptic nucleus (SON) is an important part of its physiological function since the local peptides can regulate the electrical activity of magnocellular neurons (MCNs) which possess receptors for these peptides. This direct postsynaptic action would affect the output of peptide in the neurohypophysis. Another way that these peptides can regulate MCN activity would be to modulate afferent inputs unto themselves. Although the influence of afferent inputs (inhibitory and excitatory) on SON magnocellular neuron physiology has been extensively described in the last decade, a role for these locally released peptides on synaptic physiology of this nucleus has been difficult to show until recently, partly because of the difficulty of performing stable synaptic recordings from these cells in suitable preparations that permit extensive examination. We recently showed that under appropriate conditions, oxytocin acts as a retrograde transmitter in the SON. Oxytocin, released from the dendrites of MCNs, decreased evoked excitatory synaptic transmission by inhibiting glutamate release from the presynaptic terminals. It modulated voltage-dependent calcium channels, mainly N-type and to a lesser extent P/Q-type channels, located on glutamatergic terminals. Although evidence is less conclusive, it is possible that vasopressin has similar actions to reduce excitatory transmission. This synaptic depressant effect of oxytocin and/or vasopressin, released from dendrites, would ensure that MCNs regulate afferent input unto themselves using their own firing rate as a gauge. Alternatively, it may only be a subset of afferent terminals that are sensitive to these peptides, thereby providing a means for the MCNs to selectively filter their afferent inputs. Indeed its specificity is partly proven by our observation that oxytocin does not affect spontaneous glutamate release, or GABA release from inhibitory terminals (Brussaard et al., 1996). Thus, the dendrites of MCNs of the supraoptic nucleus serve a dual role as both recipients of afferent input and regulators of the magnitude of afferent input, allowing them to directly participate in the shaping of their output. This adds to a rapidly growing body of evidence in support of the concept of a two-way communication between presynaptic terminals and postsynaptic dendrites, and shows the potential of this nucleus as a model to study such form of synaptic transmission.

Animals↗
PubMed1998

Chondroitin sulfate proteoglycan specific to retinal horizontal neurons.

ABSTRACT Proteoglycans (PGs) are a diverse group of highly glycosylated macromolecules that are implicated in the development and maintenance of neuronal circuitry. With its highly ordered, layered structure, the retina ideally serves to define the synthesis, processing, and distribution of these molecules within a specific cellular subpopulation. In retinal sections, monoclonal antibody (MAb) 6A2 immunostained a horizontal cell-specific antigen. Antigen 6A2 was expressed within abundant processes in the outer plexiform layer and in rare neurites that extend across the inner nuclear layer to the inner plexiform layer. Ultrastructurally, the antigen was localized to cisternae within horizontal cell somata, along tubulovesicular structures in dendrites, and in the perisynaptic space encircling presynaptic terminals of the cone photoreceptor triad. These findings suggest that this PG is synthesized within the horizontal cells, transported to the terminals, and released into the extracellular spaces just proximal to the synapse. Based on the focal stain in the adjacent photoreceptor cell, it is possible that antigen is pinocytosed by this cell and is concentrated at the ribbon synapse. In Western immunoblots of retinal homogenates, MAb 6A2 recognized a heterogeneous chondroitin sulfate (CS) PG (CSPG) of approximately 400-500 kDa. After sequential enzymatic removal of CS glycosaminoglycans, a major broad band of 300-500 kDa was identified by MAb 1B5, which detects CSPGs that bear uronic acid linked to unsulfated N-acetylgalactosamine as the initial disaccharide in the CS chain. Localization of this PG around presynaptic terminals of the horizontal neuron and at the ribbon synapse suggests that it may play a modulatory and sustaining role at the synapse.

Animals↗