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PubMed2000

Different localizations and functions of L-type and N-type calcium channels during development of hippocampal neurons.

Using immunocytochemical assays and patch-clamp and calcium-imaging recordings, we demonstrate that L-type and N-type calcium channels have distinct patterns of expression and distribution and play different functional roles during hippocampal neuron differentiation. L-type channels, which support the depolarization-induced calcium influx in neurons from the very early developmental stages, are functionally restricted to the somatodendritic compartment throughout neuronal development and play a crucial role in supporting neurite outgrowth at early developmental stages. N-type channels, which start contributing at later neuronal differentiation stages (3-4 DIV), are also functionally expressed in the axons of immature neurons. At this developmental stage preceding synaptogenesis, N-type (but not L-type) channels are involved in controlling synaptic vesicle recycling. It is only at later developmental stages (10-12 DIV), when the neurons have established a clear axodendritic polarity and form synaptic contacts, that N-type channels are progressively excluded from the axon. Electrophysiological recordings of single neurons growing in microislands revealed that synaptic maturation coincides with a progressive increase in N-type channels in the somatodendritic region and a progressive decrease in the N-type channels supporting glutamate release from the presynaptic terminal. These results indicate that L-type and N-type calcium channels undergo dynamic, developmentally regulated rearrangements in regional distribution and function and also suggest that different mechanisms may be involved in the sorting and/or stabilization of these two types of channels in different plasma membrane domains during neuronal differentiation.

Animals↗
PubMed1993

Rapid synaptic changes and bundling in the supraoptic dendritic zone of the perfused rat brain.

In the dendritic region of the supraoptic nucleus of young adult rats we found ultrastructural evidence of rapid (< 30 min) morphological reorganization following transcardial perfusion of the anesthetized animals with high (325 mOsm), but not with normal, osmolality (302 mOsm) balanced salt solutions. The changes observed included significant increases in dendritic bundling and increased numbers of multiple axodendritic synapses (where one presynaptic terminal contacted two or more postsynaptic dendrites). In our initial experiments the perfusion medium contained tannic acid, but when the tannic acid was omitted in a separate set of experiments, the results were both similar and more striking. These studies indicate that the plasticity previously seen in this region under physiological conditions can occur rapidly and probably involves astrocytic process withdrawal from between adjacent dendrites. This change in the distribution of astrocytic processes allows previously single synapses access to additional postsynaptic dendritic membrane. Together, increased dendritic bundling and multiple synapses may facilitate the synchronization of cell firing and, thus, hormone release.

Animals↗
PubMed1999

The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases.

A family of homologous proteins known as alpha-, beta-, and gamma-synuclein are abundantly expressed in brain, especially in the presynaptic terminal of neurons. Although the precise function of these proteins remains unknown, alpha-synuclein has been implicated in synaptic plasticity associated with avian song learning as well as in the pathogenesis of Parkinson's disease (PD), dementia with LBs (DLB), some forms of Alzheimer's disease (AD), and multiple system atrophy (MSA). Since olfactory dysfunction is a common feature of these disorders and the olfactory receptor neurons (ORNs) of the olfactory epithelium (OE) regenerate throughout the lifespan, we used antibodies specific for alpha-, beta-, and gamma-synucleins to examine the olfactory mucosa of patients with PD, DLB, AD, MSA, and controls without a neurological disorder. Although antibodies to alpha- and beta-synucleins detected abnormal dystrophic neurites in the OE of patients with neurodegenerative disorders, similar pathology was also seen in the OE of controls. More significantly, we show here for the first time that alpha-, beta-, and gamma-synucleins are differentially expressed in cells of the OE and respiratory epithelium and that alpha-synuclein is the most abundant synuclein in the olfactory mucosa, where it is prominently expressed in ORNs. Moreover, alpha- and gamma-synucleins also were prominent in the OE basal cells, which include the progenitor cells of the ORNs in the OE. Thus, our data on synuclein expression within the OE may signify that synuclein plays a role in the regeneration and plasticity of ORNs in the adult human OE.

Adult↗
PubMed2001

Prominent perikaryal expression of alpha- and beta-synuclein in neurons of dorsal root ganglion and in medullary neurons.

Synucleins (syns) are a family of small, highly conserved proteins expressed predominantly in neurons. Although the normal function of syns is unknown, alpha-syn plays a pivotal role in several neurodegenerative diseases. The expression patterns of syns have been described in several studies, but much of this information was obtained before the cloning of all four members of this family of proteins and previous studies were limited to the analysis of single species. Here, we used antibodies specific for alpha-, beta-, and gamma-syn to study the patterns of expression in human, mouse, and rat nervous systems. Significant species-specific differences were detected in the expression of all three syns throughout the neuraxis. For example, gamma-syn is highly expressed in human cortex, while it is present only at low levels in mouse and rat cortex. Moreover, in contrast to previous reports that alpha- and beta-syns are normally localized predominantly at presynaptic terminals, we demonstrate that these proteins also are abundant in the perikarya of some neurons, such as in dorsal root ganglion. Intense alpha-syn immunoreactivity also was detected in the perikarya of human neurons in raphe, hypoglossal, and arcuate nuclei. These data underscore the need for additional studies to better understand the fundamental biological mechanism(s) targeting specific proteins to axonal terminals, as disruption of this process may be involved in the formation of pathological lesions.

Animals↗
PubMed2001

Conformational properties of alpha-synuclein in its free and lipid-associated states.

alpha-Synuclein (alphaS) is a presynaptic terminal protein that is believed to play an important role in the pathogenesis of Parkinson's disease (PD). We have used NMR spectroscopy to characterize the conformational properties of alphaS in solution as a free monomer and when bound to lipid vesicles and lipid-mimetic detergent micelles. Free wild-type alphaS is largely unfolded in solution, but exhibits a region with a preference for helical conformations that may be important in the aggregation of alphaS into fibrils. The N-terminal region of alphaS binds to synthetic lipid vesicles and detergent micelles in vitro and adopts a highly helical conformation, consistent with predictions based on sequence analysis. The C-terminal part of the protein does not associate with either vesicles or micelles, remaining free and unfolded. These results suggest that one function of alphaS may be to tether as of yet unidentified partners to lipid surfaces via interactions with its C-terminal tail.

Carbon↗
PubMed2000

Review: formation and properties of amyloid-like fibrils derived from alpha-synuclein and related proteins.

Synucleinsare small proteins that are highly expressed in brain tissue and are localised at presynaptic terminals in neurons. alpha-Synuclein has been identified as a component of intracellular fibrillar protein deposits in several neurodegenerative diseases, and two mutant forms of alpha-synuclein have been associated with autosomal-dominant Parkinson's Disease. A fragment of alpha-synuclein has also been identified as the non-Abeta component of Alzheimer's Disease amyloid. In this review we describe some structural properties of alpha-synuclein and the two mutant forms, as well as alpha-synuclein fragments, with particular emphasis on their ability to form beta-sheet on ageing and aggregate to form amyloid-like fibrils. Differences in the rates of aggregation and morphologies of the fibrils formed by alpha-synuclein and the two mutant proteins are highlighted. Interactions between alpha-synuclein and other proteins, especially those that are components of amyloid or Lewy bodies, are considered. The toxicity of alpha-synuclein and related peptides towards neurons is also discussing in relation to the aetiology of neurodegenerative diseases.

Amyloid↗
PubMed1998

Recruitment of a nicotinic acetylcholine receptor mutant lacking cytoplasmic tyrosine residues in its beta subunit into agrin-induced aggregates.

During synaptogenesis at the vertebrate skeletal neuromuscular junction, acetylcholine receptors (AChRs) form high-density aggregates opposite the presynaptic terminal in response to nerve-derived agrin. Agrin has been shown to stimulate tyrosine phosphorylation of a muscle-specific receptor tyrosine kinase MuSK and of the AChR beta subunit, and tyrosine kinase inhibitors and a tyrosine kinase-deficient mutant of MuSK prevent AChR aggregation. To evaluate the role of tyrosine phosphorylation of the AChR beta subunit in receptor aggregation, we replaced all three putative cytoplasmic tyrosine residues of the AChR beta subunit with phenylalanine residues and expressed the mutant receptors in cultured myotubes. Upon agrin treatment, transfected myotubes formed AChR aggregates that contained receptors with mutant beta subunits. Thus, AChRs can be recruited into agrin-induced specializations by protein-protein interactions that do not depend on tyrosine phosphorylation of the AChR beta subunit.

Agrin↗
PubMed1998

Purification of human fetal hippocampal neurons by flow cytometry for transplantation.

We have established primary cultures, highly enriched in neurons, from the hippocampus of human fetal brains at 20-23 gestational weeks. More than 80% of cells were viable when seeded. Neurons were isolated from primary cultures by flow cytometry to a high degree of purity, as demonstrated by immunocytochemical staining. FACS scanning analysis using a DNA-staining dye showed that hippocampal neurons did not divide in culture. To demonstrate that FACS-sorted neurons can be transplanted and integrated into the host brain, neuron-enriched primary culture from human fetal striatum was infected with a viral-mediated vector containing a reporter gene, beta-galactosidase. Striatal neurons were subsequently purified by flow cytometry and transplanted into the striatum of rats. Following transplantation, the rat brains were processed for beta-galactosidase histochemistry and electron microscopy. Beta-galactosidase expression indicates that transplanted human neurons survived in the host and were metabolically active. The transplanted neurons received synaptic inputs, as judged from the presence of presynaptic terminals on their surface. Our study demonstrates connectivity between transplanted human fetal primary neurons and host tissue at the ultrastructural level. Our results support the feasibility of ultimately transplanting neurons into humans as a possible treatment for recovery of the nervous system (e.g., neurodegenerative diseases).

Animals↗
PubMed1996

Increased density of multiple-head dendritic spines on medium-sized spiny neurons of the striatum in rats reared in a complex environment.

It has generally been assumed that new synapses added to various brain regions in response to experience are equivalent to those already in existence. Theorists have recently posited that synaptic configurations involving multiple associated contacts may facilitate plastic change. The number of multiple-headed dendritic spines on medium-sized spiny neurons in the rat dorsolateral corpus striatum was determined following rearing in environments differing in complexity. Postweaning rats were either housed as a group in a toy- and object-filled environment or housed individually in standard laboratory cages for 30 days. Dendritic segments of Golgi-Cox impregnated Type I spiny neurons of the complex environment housed rats had approximately 60% more multiple-head spines than those of the individually caged animals. Multiple-head spines may reflect parallel synaptic contacts that modify relative strengths of existing connections or connections with a novel presynaptic terminal that alter the neuron's pattern of connections.

Animals↗
PubMed1989

Presynaptic cholinergic action in the hippocampus.

The hippocampus is among the regions in the brain richest in M1 cholinergic receptors. Topical application of acetylcholine (ACh) onto hippocampal slices produces a characteristic complex response consisting of a depolarization, an increase in input resistance especially upon depolarization and a blockade of a slow afterhyperpolarization (AHP). The first two of these responses can be recorded also in non-cholinergic septal neurons in an area which contains about 8% of the M1 muscarinic receptors found in the hippocampus. The responses of hippocampal but not septal neurons to ACh involve an increase in the spontaneous synaptic activity and a decrease in evoked responses to afferent stimulation. The dissociated hippocampal culture was used to study these presynaptic effects. The neurons in culture possess muscarinic receptors which develop gradually over a period of several weeks after plating. ACh rarely depolarizes hippocampal neurons in culture. Instead, it causes an increase in spontaneous discharge of small postsynaptic currents (PSC's) and a marked decrease of large, evoked PSC's. In some cultured hippocampal cells ACh reduced ICa without affecting any of several outward K currents studied. It is suggested that ACh reduces evoked activity by reducing Ca currents at presynaptic terminals.

Acetylcholine↗
PubMed1990

The low KM-phosphodiesterase inhibitor denbufylline enhances neuronal excitability in guinea pig hippocampus in vitro.

The actions of the phosphodiesterase inhibitor denbufylline on the excitability of hippocampal neurons were investigated by means of extracellular and intracellular recordings. Denbufylline, which has been shown to selectively inhibit a low KM, Ca2+/calmodulin-independent phosphodiesterase isozyme, concentration-dependently increased the amplitude of the extracellularly recorded CA1 population spike evoked by electrical stimulation of the Schaffer collateral/commissural pathway. Concentration-response-curves yielded an EC50 for denbufylline of 0.76 microM. In comparison, the non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) also produced an increase in the amplitude of the population spike. From the concentration-response-curve, which was steeper than that of denbufylline, an EC50 for IBMX of 1.04 microM was obtained. However, despite their similar EC50 values, denbufylline was found to be significantly more potent at lower concentrations (less than or equal to 300 nM) than IBMX. Intracellular recordings from CA1 pyramidal cells revealed postsynaptic actions of denbufylline (300 nM) as indicated by a small drug-induced depolarization (2-5 mV) associated with an increase in membrane input resistance by 10-20%. In addition, denbufylline blocked the accommodation of trains of action potentials evoked by the injection of depolarizing current pulses. The results suggest i) that accumulation of adenosine-3',5'-monophosphate (cAMP) in the postsynaptic cell and/or in the presynaptic terminal produced by blockade of phosphodiesterases leads to enhanced synaptic transmission in the CA1 area of the hippocampus and ii) that a low KM, Ca2+/calmodulin-independent cAMP-phosphodiesterase is an important component involved in the regulation of the intracellular cAMP level at synapses of central nervous system neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Chronic treatment with D1 and D2 dopamine receptor agonists: combined treatments interact to differentially affect brain levels of monoamines.

Recent evidence of functional interactions between D1 and D2 dopamine receptor subtypes has led to the concept that many of the behavioural effects of dopamine agonists occur only with activation of both receptor subtypes. Thus, combined treatment with dopamine agonists selective for each of the D1 and D2 receptors may be an effective therapy for Parkinson's disease, chiefly characterized by loss of central dopamine-containing neurons. In addition, recent hypotheses of the possible pathogenesis of this disorder have suggested that metabolism of dopamine by monoamine oxidase in the presynaptic terminal may contribute to the loss of dopaminergic cells, through the production of reactive by-products. Therefore, the effects of chronic (15 day) treatment of rats with different doses of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a D2 receptor agonist), SKF 38393 (a D1 receptor partial agonist) or combinations of both drugs on levels of brain monoamines and some of their acidic metabolites were investigated. Little or no effects of the drugs were observed on measures of dopamine or noradrenaline when given separately, while each selective agonist dose-dependently reduced serotonin levels. Combined treatment with the two agonists produced profound effects on the catecholamines, but with no effect on 3,4-dihydroxyphenylacetic acid, the metabolite of dopamine produced by monoamine oxidase. In addition, the effects of combined treatment on serotonin levels were opposite of those of the drugs given independently. Concomitant treatment of animals with both D1 and D2 receptor agonists can therefore increase tissue levels of dopamine without increasing the potentially harmful metabolism of dopamine by monoamine oxidase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1981

The nervous system of Microstomum lineare (Turbellaria, Macrostomida). II. The ultrastructure of synapses and neurosecretory release sites.

The ultrastructure of release sites of neurochemical messenger substances in the microturbellarian Microstomum lineare was examined. Aminergic neurites form conventional synapses and synapse-like structures (SLS). Variants of true synapses include: "single" synapses with symmetric pre- and postsynaptic densities, "shared" synapses, i.e., contacts between 1 pre- and 2 postsynaptic fibres, en passant synapses between parallel axonal membranes, and synapses without thickenings having only clustered vesicles in the presynaptic terminal. SLS on a nerve cell soma or facing an intercellular stromal channel near muscles are described. Peptidergic neurites containing large granular vesicles (LGV) from synaptoids and signs of putative neurosecretory release. Synaptoids between neurites and between neurite and muscle have lucent vacuoles (about 100 nm) and dense material at the contact site. In en passage synaptoids dense-core vesicles are embedded in electron-dense material at the contact site. Putative signs of release of neurosecretory material other than "typical" exocytosis have been observed.

Amines↗
PubMed1982

Intrinsic neurons and neural connections of the pineal organ of the house sparrow, Passer domesticus, as revealed by anterograde and retrograde transport of horseradish peroxidase.

In Passer domesticus, intrapineal nerve cells were labeled by uptake of microiontophoretically administered horseradish peroxidase (HRP). Unipolar nerve cells with a dichotomously branching stem process are the main source of the dominant pinelaofugal component of the pineal tract, whereas multipolar and bipolar neurons appear to represent interneurons. HRP-Labeled nerve fibers are observed in the distal division (end-piece) of the pineal organ; they can be regarded either as processes of intrapineal neurons or projections of pinealopetal axons originating from central neurons. Furthermore, scattered labeled nerve fibers occur in different portions of the pineal stalk. Nerve fibers containing HRP were also demonstrated in the medial and lateral divisions of the habenular complex and in the periventricular layer of the hypothalamus; these axons apparently represent anterogradely labeled pinealofugal elements. On the other hand, retrogradely labeled neurons were found in the medial habenular complex and in the periventricular hypothalamic gray near the paraventricular nucleus, indicating that the pineal organ receives a pinealopetal innervation arising from the central nervous system. Ultrastructurally, the neuropil of the pineal organ of P. domesticus displays single basal processes of pinealocytes containing synaptic ribbons in association with clear synaptic vesicles. Occasionally, conventional synapses were observed the presynaptic terminals of which exhibit granular inclusions. The pineal tract consisting of four to six spatially separated fiber bundles comprises mainly unmyelinated elements accompanied by only few myelinated axons. The functional role of the neural apparatus revealed in the present study is discussed in context with the humoral (hormonal) control of circadian functions; the latter type of activity has been shown to exist in the pineal organ of P. domesticus (Zimmerman 1976).

Animals↗
PubMed1987

Development of the electromotor system in Torpedo marmorata: cationic staining of the electric organ.

The electric organs of embryonic Torpedo marmorata have been reacted with three cationic stains to evaluate the appearance and distribution of anionic sites. Ruthenium red, alcian blue and lysozyme were used at different pHs and found to react in a time-related manner to anionic components within the interelectrocyte space. The basal lamina covering the ventral electrocyte surface possesses the greatest number of anionic sites whereas growth cone, presynaptic terminal and glial membranes displayed almost no staining. Since this lamina serves as the exclusive substrate for ingrowing neurites during synaptogenesis, the results are consistent with the idea that charge distribution on the membrane surface may provide a necessary cue for neurite motility, extension and eventual synaptogenesis.

Animals↗
PubMed1982

Morphological study on the regeneration of the retina in the rainbow trout after ouabain-induced damage: evidence for dedifferentiation of photoreceptors.

The retina of the rainbow trout is capable of marginal regeneration after ouabain-induced degeneration (intraocular injection of 5 microliters 10(-4) M ouabain). In the central area where the pigment epithelium proliferates to a multicellular layer, the neural retina does not regenerate up to 182 days after injection of ouabain. The regeneration process begins in the marginal growth zone with an increase in the mitotic rate; the growth zone itself is not damaged after ouabain administration. The proliferate differentiates with time into a newly layered retina; this portion of the retina is called the paramarginal zone, i.e., the "first" regenerated zone. The paramarginal zone is arranged concentrically to the retinal margin. Cells surviving ouabain administration, located outside, although close to the margin and occurring mostly in the outer nuclear layer, reveal signs of dedifferentiation: loss of the outer segment, amalgamation of the presynaptic terminal with the perikaryal cytoplasm, alteration of cell shape, and mitotic activity. The area in which these dedifferentiation processes are observed is found adjacent and concentric to the paramarginal zone; it is thinner than the latter and incompletely structured ("second" regenerated zone). The third zone adjoins the second zone and is characterized by folds, which were described previously as "rosettes". Extracellular microtubule-like structures, which are found between the horizontal cells in the normal retina of the rainbow trout, regenerate only sparsely in the paramarginal zone, whereas they are lacking in the incompletely regenerated zones.

Animals↗
PubMed1983

An ultrastructural study of the development of afferent and efferent synapses on outer hair cells of the guinea pig organ of Corti.

The guinea pig organ of Corti was studied using transmission electron microscopy, the second turn of the cochlea being examined at various ages between 20 days before birth and 30 days postnatal. Outer hair cells were examined at each of these ages. At all ages studied, the efferent (presynaptic) terminals are large and are packed with synaptic vesicles, whereas the afferent (postsynaptic) terminals are generally smaller, with a relatively small number of vesicles. During development, the subsynaptic cistern changes from a fragmented, diffuse profile extending over 50-70% of the length of the efferent contact zones, to a continuous, compact structure spanning neighbouring synapses. Synaptic vesicles in the efferent terminals are predominantly rounded in early development, flattened vesicles appearing postnatally. The synaptic bodies at afferent synapses do not change noticeably during development. Quantitative analysis revealed that the area of efferent terminals and the length of their active zone increase with increasing age, the same parameters decreasing in afferent terminals. Synaptic vesicles in the efferent terminals decrease in diameter, but remain constant in afferent terminals, with increasing age. The number of hair cell membrane invaginations decreases as development proceeds.

Afferent Pathways↗
PubMed1976

A critical evaluation of the relationship between the presynaptic network, synaptic vesicles and dense projections in central synapses.

Synapses of the oculomotor nucleus of Echidna have been examined ultrastructurally with the aim of integrating data obtained from osmicated and nonosmicated PTA stained material. Particular emphasis has been laid on the relationship between the synaptic vesicles of the osmicated material and the presynaptic network and vesicular grid of the PTA material. This relationship has been explored qualitatively by examining osmicated material of varying qualities of fixation. Such material contains dense projections in addition to synaptic vesicles, and various vesicular network appearances. A variety of measurement techniques have shown that the PTA network is characterised by reticular strands, spaces, and regular hexagonal units smaller than vesicles, these observations prompting the formulation of a "vesicle-network coincidence" model of the presynaptic terminal. This model has been tested by tracing the profiles of vesicles within the PTA network and comparing their size and shape frequency distributions with those of osmicated synaptic vesicles. The distributions have been found to be essentially similar, suggesting that vesicles can be located within the network, and that the hexagonal network units are formed only in the presence of an underlying vesicular matrix. Additionally, the following points have emerged: 1) the dense projections in the two types of material appear to be quivalent; 2) a loose correlation exists between dense projections and vesicles in osmicated terminals, increase in the area of the dense projections being associated with a decrease in the area of the vesicles; 3) network and dense projection units are similar. In view of the similarity between network and dense projection units, the demonstrated vesicular basis of the network raises the question of whether dense projections are entirely independent structures, or whether they depend in part for their existence on the nearby presence of synaptic vesicles.

Animals↗