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PubMed1992

The synapsin I brain distribution in ischemia.

We examined the distribution of synapsin I in the gerbil brain and investigated ischemic damage of presynaptic terminals immunohistochemically by using this protein as a marker protein of synaptic vesicles. The reaction for synapsin I in normal gerbil brain is exclusively localized in the neuropil, and other brain structures such as neuronal soma, dendrites, axon bundles, glia and endothelial cells exhibited little immunoreactivity. In a reproducible gerbil model of unilateral cerebral ischemia, ischemic loss of synapsin I immunoreactivity in the affected hemisphere was confined to the area exhibiting overt infarction, where the breakdown of this protein was also confirmed by the immunoblot analysis, and noted much later than that of microtubule-associated protein 2 immunoreactivity, which was demonstrated in neuronal soma and dendrites. In the non-affected hemisphere, selective damage of presynaptic terminals due to Wallerian degeneration and subsequently occurring resynaptogenesis at the molecular layer of the dentate gyrus were clearly demonstrated as a loss and recovery of immunoreaction for synapsin I, respectively. In a gerbil model of bilateral cerebral ischemia, immunoreaction for synapsin I was persistently preserved after seven days to two months recirculation following a brief period of global forebrain ischemia in the CA1 region of the hippocampus, where delayed neuronal death was consistently observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Chronic ethanol exposure enhances [3H]GABA release and does not affect GABAA receptor mediated 36Cl uptake.

Chronic ethanol treatment (CET) produces a permanent reduction in hippocampal long-term potentiation (LTP). The CET produced reduction of LTP can be eliminated acutely by pharmacological blockade of gamma-aminobutyric acid (GABA)ergicA synaptic transmission with the specific antagonist, bicuculline methiodide. Since LTP induction is normally modulated by activation of GABAergic synaptic transmission, we hypothesized that CET reduced LTP by enhancing either postsynaptic GABAA channel function or GABA release from presynaptic terminals. In the present study, we examined the long term effects of CET on GABAA channel function by measuring the efficacy of GABA to stimulate and bicuculline to antagonize GABA-stimulated 36Cl- uptake in hippocampal and cortical membrane preparations. CET did not affect basal uptake of chloride or the efficacy of either GABA or bicuculline at the GABAA channel. We next measured the long term effects of CET on basal and stimulated GABA release. When basal and electrically-stimulated [3H]GABA release were measured in superfused hippocampal slices, stimulated release was increased by 30% in CET rats. Basal release was unaffected. Thus it appears that CET may be reducing LTP by enhancing plasticity-related GABA release from presynaptic terminals.

Animals↗
PubMed1997

Presynaptic nicotinic ACh receptors.

Nicotinic ACh (nACh) receptors in the CNS are composed of a diverse array of subunits and have a range of pharmacological properties. However, despite the fact that they are ligand-gated cation channels, their physiological functions have not been determined. This has led to increased interest in presynaptic nACh receptors that act to modulate the release of transmitter from presynaptic terminals.

Animals↗
PubMed2003

Subcellular distribution of L-type Ca2+ channels responsible for plateau potentials in motoneurons from the lumbar spinal cord of the turtle.

L-type calcium channels mediate the persistent inward current underlying plateau potentials in spinal motoneurons. Electrophysiological analysis shows that plateau potentials are generated by a persistent inward current mediated by low threshold L-type calcium channels located in the dendrites. As motoneurons express L-type calcium channels of the CaV1.2 and CaV1.3 subtypes, we have investigated the subcellular distribution of these channels using antibody labelling. The plateau generating a persistent inward current is modulated by the activation of metabotropic receptors. For this reason, we also examined the relationship between CaV1.2 and CaV1.3 subunits in motoneurons and presynaptic terminals labelled with antibodies against synapsin 1a. Motoneurons in the spinal cord of the adult turtle were identified as large neurons, immunopositive for choline acetyltransferase, located in the ventral horn. In these neurons, CaV1.2 subunits were present in the cell bodies and axons. Patches of CaV1.3 subunits were seen in association with the cell membrane of the somata and both the proximal and distal dendrites. Double labelling with an antibody against synapsin 1a showed that CaV1.3 subunits, but not CaV1.2 subunits, were always located at synaptic sites. The distribution of CaV1.2 and CaV1.3 strongly suggests that the persistent inward current underlying plateau potentials in spinal motoneurons is mediated by CaV1.3 and not by CaV1.2. Our findings also show that CaV1.3 may be located in the somatic and dendritic membrane adjacent to particular presynaptic terminals.

Animals↗
PubMedDate not supplied

Synaptic contacts in schizophrenia: studies using immunocytochemical identification of dopaminergic neurons.

Immunocytochemical identification of dopaminergic neurons was performed using an immunoperoxidase method employing antibodies to tyrosine hydroxylase. The ultrastructure of synaptic contacts on dopaminergic (tyrosine hydroxylase immunopositive (TP) cells) neurons was investigated in the substantia nigra in the brains of four patients with schizophrenia and three mentally healthy subjects (controls). The substantia nigra of schizophrenia patients differed from control material in showing the following changes in the ultrastructure of presynaptic terminals contacting TP neurons: reductions in the size of terminals with dense matrix and poorly distinguished vesicles; swelling of terminals with small numbers of vesicles displaced from the active zone of the synapse; hyperplasia of mitochondria in some presynaptic boutons; appearance of membranous lamellar structures within or adjacent to presynaptic boutons. These changes to terminals were located mostly on the distal (small and intermediate) TP dendrites in the compact zone of the substantia nigra, where nearly all the dendrites detected belonged to dopaminergic neurons and the altered terminals formed asymmetrical contacts with short active zones. In the reticular part of the substantia nigra of schizophrenic patients, changes in the ultrastructure of presynaptic terminals were relatively rare; altered terminals contacted both tyrosine hydroxylase immunopositive as well as with the tyrosine hydroxylase immunonegative dendrites located in this structure.

Adolescent↗
PubMed2006

Permethrin, but not deltamethrin, increases spontaneous glutamate release from hippocampal neurons in culture.

Pyrethroid insecticide modulation of the voltage-gated sodium channel (VGSC) is proposed to underlie their effects on neuronal excitability. However, some in vitro evidence indicates that target sites other than VGSCs could contribute to pyrethroid disruption of neuronal activity. VGSC-independent, pyrethroid-induced changes in neurotransmitter release were examined to investigate the possibility that target sites other than VGSCs contribute to pyrethroid effects. Using whole-cell patch clamp recordings, deltamethrin and permethrin effects on glutamate-mediated miniature excitatory postsynaptic currents (mEPSCs) from pyramidal neurons in mixed hippocampal cultures were examined. In the presence of the VGSC antagonist tetrodotoxin, the type I pyrethroid permethrin (10 microM) increased the average frequency of mEPSCs from a basal level of 1.0+/-0.4 to 3.5+/-0.6 Hz, with peak frequency of 9.9+/-1.5 Hz (n=6). Permethrin did not affect the distribution of current amplitudes, indicating that permethrin increased the probability of glutamate release at the presynaptic terminal without effects on postsynaptic responses. Removal of calcium from the extracellular solution following the induction of the permethrin-mediated effect decreased mEPSC frequency (6.8+/-1.8 Hz, n=3) to near control levels (1.9+/-0.8 Hz for control versus 2.5+/-0.6 Hz for permethrin minus Ca(2+), respectively). However, the N- and P/Q-type voltage-gated calcium channel antagonist omega-conotoxin MVIIC had no effect on the permethrin-dependent increase in mEPSC frequency. In contrast to permethrin, the type II pyrethroid deltamethrin (10 microM) failed to affect mEPSC frequency. These results indicate that permethrin causes a calcium-dependent increase in glutamate release from hippocampal neurons that is independent of effects on voltage-gated sodium or N- or P/Q-type voltage-gated calcium channels. The data indicate that permethrin increases mEPSC frequency via an alteration in intracellular calcium dynamics at the presynaptic terminal.

Action Potentials↗
PubMed1996

Giant, TTX-insensitive, inhibitory postsynaptic currents in cultured rat spinal cord and medullary neurons.

1. In whole cell patch-clamp studies on cultured rat embryonic spinal cord and medullary neurons bathed in tetrodotoxin, DL-2-amino-5-phosphonovaleric acid, and 6-cyano-7-nitroquinoxaline-2,3-dione, large and long-lasting spontaneous inhibitory postsynaptic currents were occasionally recorded. The amplitudes of these events were 1 order of magnitude larger than those of spontaneous miniature inhibitory postsynaptic currents. Because these large currents had reduced amplitudes in calcium-free saline and in solutions containing glycinergic or GABAergic antagonists, we conclude that they were probably produced by large and prolonged release of glycine and/or 4-amino-n-butyric acid (GABA), which subsequently bind to their postsynaptic receptors. 2. The frequency of spontaneous miniature postsynaptic currents increased dramatically during the long, slow decay phase of these large postsynaptic currents. Considering the requirement for extracellular calcium for the occurrence of these large responses, we hypothesize that this increased frequency reflected an increased intracellular calcium concentration in the presynaptic terminal. 3. Similar evidence for large inhibitory postsynaptic currents and prolonged transmitter release was observed in cell-attached patches, which also exhibited the smaller, spontaneous miniature inhibitory postsynaptic currents, suggesting that these large events are properties of single synaptic terminals. 4. A comparison of the properties of these large inhibitory postsynaptic currents recorded in whole cell mode or cell-attached patches showed no statistically significant differences. The overall mean values, then, are 13.9 +/- 1.6 (SE) ms and 4.5 +/- 0.5 s for the 10-90% rise time and duration, respectively. Furthermore, these large events had amplitudes that were 11-fold larger than the mean amplitude of the miniatures (i.e., mean amplitude ratio of 10.8 +/- 0.5). 5. Periodic large increases in the frequency of spontaneous miniature inhibitory postsynaptic currents occurred in both cell-attached patches and in the whole cell mode, and these increases were only sometimes associated with the large inhibitory postsynaptic currents. The rhythmicity in both recording configurations had similar temporal characteristics, with average interburst intervals of 5 and 12-14 s. Presumably these bursts of spontaneous miniature postsynaptic currents reflected periodic oscillations in the Ca2+ concentration in presynaptic terminals. 6. Both the probability and the frequency of occurrence of large inhibitory postsynaptic currents doubled during the 7-day period of time in culture when experiments were performed, suggesting that these large currents may play a role during development.

Animals↗
PubMed2005

Differential appearance of dynamin in constitutive and regulated exo-endocytosis: a single-cell multiplex RT-PCR study.

Neurons in the central nervous system establish, via their axons and dendrites, an extended network that allows synaptic transmission. During developmental maturation and process outgrowth, membrane turnover is necessary for the enlargement and subsequent growth of axons and dendrites from the perikarya to the target cell (constitutive exocytosis/endocytosis). After targeting and synapse formation, small synaptic vesicles are needed for the quantal release of neurotransmitters from the presynaptic terminal with subsequent recycling by regulated exocytosis/endocytosis. An investigation of the onset of the appearance of mRNA and protein in dissociated cultures of neurons from mouse hippocampus or from chick retina has shown an early abundance of proteins involved in exocytosis, such as syntaxin 1, SNAP-25, and synaptotagmin 1, whereas dynamin 1, a protein necessary for clathrin-mediated endocytosis, can be detected only after neurons have established contacts with neighboring cells. The results reveal that constitutive membrane incorporation and regulated synaptic transmitter release is mediated by the same neuronal proteins. Moreover, the data exclude that dynamin 1 takes part in constitutive recycling before synapse formation, but dynamin 2 is present at this stage. Thus, dynamin 2 may be the constitutive counterpart of dynamin 1 in growing neurons. Synapse establishment is linked to an upregulation of dynamin 1 and thereby represents the beginning of the regulated recycling of membranes back into the presynaptic terminal.

Animals↗
PubMed1985

Proteins rapidly transported to the synapses of a single identified neuron of Aplysia californica.

The cell body of R2, a giant cholinergic neuron of Aplysia californica, resides in the abdominal ganglion, whereas its synapses are on thousands of unicellular mucus glands located in the skin. Due to the great spatial separation between the site of macromolecular synthesis and the presynaptic terminals, rapid axonal transport can be used to segregate synaptic proteins from those to be used elsewhere in the cell. The proteins of R2 were labeled by incubating the abdominal ganglion in [35S]methionine for 5 hr in a chamber separated from the rest of the isolated central nervous system. After 50 hr, 28 radiolabeled proteins were reproducibly found by one- and two-dimensional polyacrylamide gel electrophoresis to be transported to the distal regions of peripheral nerves P6, P7, and P8 that innervate the parapodia and middle body wall. We are sure that R2 is the source of these proteins since radioautography of sections taken throughout the nervous system, complemented by cobalt tracings, showed that R2 is the only neuron in the abdominal ganglion with axons in these nerves. Nine of the 28 transported proteins are glycoproteins since they were also labeled after injecting R2's cell body with [3H]-L-fucose. There is evidence that the proteins and glycoproteins are destined for R2's presynaptic terminals. For example, in experiments in which the body wall and parapodium remained attached to the nerves, the proteins were transported to the skin region that contains the glands. Moreover, analyses of the distribution of the rapidly transported proteins by qualitative radioautography and by extrusion of axoplasm indicated that none are constituents of the axolemma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effect of chemical destruction of adrenergic neurones on some cholinergic mechanisms in adult rat sympathetic ganglia.

Rats were treated for 2-6 weeks with guanethidine after which their superior cervical ganglia were removed. Ganglionic tyrosine hydroxylase and alpha-bungarotoxin binding sites were reduced by the guanethidine treatment indicating adrenergic cell body destruction. Choline acetyltransferase activity and acetylcholine content of ganglia were not clearly changed by the guanethidine treatment, indicating that the drug does not destroy presynaptic terminals and that these presynaptic indicators do not adapt markedly to postsynaptic loss. The cholinesterase in the ganglia was reduced by guanethidine treatment, but such ganglia retained their ability to accumulate surplus acetylcholine when they were incubated with physostigmine. This is interpreted as indicating surplus acetylcholine accumulation is a presynaptic phenomenon. Choline uptake by resting ganglia was not reduced as a result of guanethidine treatment nor was it affected by preganglionic denervation. This is interpreted as indicating that during rest, choline uptake is into supporting cells or intraganglionic cells rather than cholinergic nerve terminals or adrenergic cell bodies.

Acetylcholine↗
PubMed1990

Adsorption of aminopyridines to phosphatidylserine membranes.

Aminopyridines belong to the class of compounds which facilitate synaptic transmission at low calcium concentration, an effect associated with the block of K+ channels, enhanced entry of calcium into presynaptic terminals and greater release of transmitter. We have measured the zeta-potential of phosphatidylserine vesicles in the presence of aminopyridines and some related compounds in order to relate the strength of association of the aminopyridines with their biological effectiveness. The dependence of zeta-potential on the concentration of aminopyridines was analyzed in terms of the Langmuir-Stern-Grahame adsorption model. The rank order of the association constants (in M-1) obtained in the study was as follows: 3,4-diaminopyridine (6.5), 4,5-diaminopyrimidine (3.8), 4-aminopyridine (2.6), 3-aminopyridine (1.8), 2-aminopyridine (1.6), 4-dimethylaminopyridine (0.5), 4-aminopyridine methiodide (0.2), and, as control, calcium (12.1). The comparison of association constants with published results of the electric potential maps obtained by the CNDO/2 method suggests that binding to phosphatidylserine membrane increases with the density of excess charge on the protonated aminopyridine ring. We find that the sequence of potencies of aminopyridines in blocking K+ channels, in releasing transmitter, and in the shifts of calcium concentration dependence of synaptic transmission are about the same as the sequence of association constants with the phosphatidylserine membrane. Assuming that the binding domain for aminopyridines in the presynaptic terminal has similar adsorption properties as the phosphatidylserine membrane, we estimate the electric potential difference between the domain and the external solution to be between -300 and -340 mV.

Adsorption↗
PubMed1996

Presynaptic phosphoprotein B-50/GAP-43 in neuronal and synaptic plasticity.

B-50/GAP-43 is a growth-associated phosphoprotein enriched in growth cones and in the presynaptic terminal. The expression of the protein is restricted to the nervous system and is highest in the first week after birth. In adult brain, B-50 is enriched in areas with high plasticity. The regulation of expression of the B-50 gene occurs both at the transcriptional and post-transcriptional level by unknown mechanisms. The gene contains 2 regions displaying promoter activity, the most 3' of which (P2) is the active on in vivo. Expression of B-50 in non-neuronal cells results in filopodial extensions whereas antibodies or antisense oligo's to B-50 prevent neurite outgrowth. The protein is important for neuronal pathfinding. Several post-translational modifications have been described, ADP-ribosylation and palmitoylation in the membrane binding domain, phosphorylation by PKC, casein kinase II and phosphorylase kinase, and dephosphorylation by several phosphatases, among which is calcineurin. Interactions of B-50 have been described with calmodulin, PIP kinase, F-actin, and phospholipids. Recent studies indicate that the phosphorylation state and amount of calmodulin bound to B-50 regulate the rate of transmitter release. Induction of long-term potentiation by high frequency stimulation of hippocampal slices results in an increased state of B-50 phosphorylation. This will increase the amount of free calmodulin in the presynaptic terminal and increase the amount of transmitter released. Although B-50 is involved in seemingly unrelated forms of neuronal plasticity, neurite outgrowth and transmitter release, our unifying hypothesis is that the protein plays an (unknown) essential, modulatory role in membrane expansion.

Animals↗
PubMed1994

Synaptic terminal coverage of primate triceps surae motoneurons.

This study examined the synaptic terminal coverage of primate triceps surae (TS) motoneurons at the electron microscopic level. In three male pigtail macaques, motoneurons were labeled by retrograde transport of cholera toxin-horseradish peroxidase that was injected into TS muscles bilaterally and visualized with tetramethylbenzidine stabilized with diaminobenzidine. Somatic, proximal dendritic, and distal dendritic synaptic terminals were classified by standard criteria and measured. Overall and type-specific synaptic terminal coverages and frequencies were determined. Labeled cells were located in caudal L5 to rostral S1 ventral horn and ranged from 40 to 74 microns in diameter (average, 54 microns). The range and unimodal distribution of diameters, the label used, and the presence of C terminals on almost all cells indicated that the 15 cell bodies and associated proximal dendrites analyzed here probably belonged to alpha-motoneurons. Synaptic terminals covered 39% of the cell body membrane, 60% of the proximal dendritic membrane, and 40% of the distal dendritic membrane. At each of these three sites, F terminals (flattened or pleomorphic vesicles, usually symmetric active zones, average contact length 1.6 microns) were most common, averaging 52%, 56%, and 58% of total coverage and 56%, 57%, and 58% of total number of cell bodies, proximal dendrites, and distal dendrites respectively. S terminals (round vesicles, usually asymmetric active zones, average contact length 1.3 microns) averaged 24%, 29%, and 33% of coverage and 33%, 35%, and 36% of number at these three sites, respectively. Thus, S terminals were slightly more prominent relative to F terminals on distal dendrites than on cell bodies. C terminals (spherical vesicles, subsynaptic cisterns associated with rough endoplasmic reticulum, average contact length 3.5 microns) constituted 24% and 11% of total terminal coverage on cell bodies and proximal dendrites, respectively, and averaged 11% and 6% of terminal number at these two locations. M terminals (spherical vesicles, postsynaptic Taxi bodies, some with presynaptic terminals, average contact length 2.7 microns) were absent on cell bodies and averaged 3% and 7% of total coverage and 2% and 5% of terminals on proximal and distal dendrites, respectively. Except for M terminals, which tended to be smaller distally, terminal contact length was not correlated with location. Total and type-specific coverages and frequencies were not correlated with cell body diameter. Primate TS motoneurons are similar to cat TS motoneurons in synaptic terminal morphology, frequency, and distribution. However, primate terminals appear to be smaller, so that the fraction of membrane covered by them is lower.

Animals↗
PubMed1998

Potentiation of transmitter release by protein kinase C in goldfish retinal bipolar cells.

1. We examined whether transmitter release could be modified by the activation of protein kinase C (PKC) of retinal bipolar cells. A bipolar cell with a large axon terminal was isolated from the goldfish retina. The presynaptic Ca2+ current was measured under whole-cell voltage clamp, and the released transmitter (probably glutamate) was detected electrophysiologically by using the response of NMDA receptors of catfish horizontal cells as a reporter. 2. Transmitter release was potentiated by a PKC activator, phorbol 12-myristate 13-acetate (PMA), but not by an ineffective phorbol ester, 4alpha-phorbol 12,13-didecanoate. A PKC inhibitor, bisindolylmaleimide I, did not affect the transmitter release by itself but blocked the PMA-induced potentiation of transmitter release. These results suggest that the actions of PMA were mediated via the activation of PKC. 3. Introduction of 5 mM EGTA into the presynaptic terminals of bipolar cells revealed two separate components of transmitter release. A rapid component was triggered immediately after depolarization while a slow component appeared with a delay. Application of PMA selectively potentiated the slow component without affecting the Ca2+ dependence of exocytosis. 4. We suggest that the activation of PKC may modify the recruitment process of synaptic vesicles in retinal bipolar cells.

Animals↗
PubMed1992

Fine structure of presynaptic axonal terminals in sympathetic autonomic ganglia of aging and diabetic human subjects.

The neuropathologic changes that may underlie autonomic nervous system dysfunction in nondiabetic elderly human subjects or as a complication of diabetes have been systematically examined in sympathetic ganglia of a series of autopsied human subjects. As in animal models of aging and diabetes, enormously swollen terminal axons were found closely apposed to the perikarya of principal sympathetic neurons in prevertebral superior mesenteric sympathetic ganglia of aged and diabetic human subjects. Dystrophic axons consisted of two stereotyped forms: the first was composed of large numbers of misaligned aggregates of neurofilaments surrounded by variable numbers of small dense core vesicles; the second was characterized by large numbers of mitochondria, vacuoles, and dense and multivesicular bodies. The fine structural characteristics of neuroaxonal dystrophy, its predilection for prevertebral rather than paravertebral sympathetic ganglia, and the tendency for multiple dystrophic axons to cluster preferentially around selected neurons were identical in aged and diabetic human ganglia and were similar to changes seen in animal models of aging and diabetes. Neither diabetic nor aging ganglia demonstrated evidence of neuronal degeneration. Such structural changes may represent a degenerative influence of diabetes and aging on the normal remodeling of nerve terminals in autonomic ganglia, i.e., the continually ongoing process of turnover and replacement of axonal terminals. Similarity of lesions in human diabetes and aging suggests the possibility of pathogenetic mechanisms that are common to diabetes and the aging process. The substantial parallels between humans and animal models provide support for the validity of testing some proposed pathogenetic mechanisms directly in animal models.

Adolescent↗
PubMed1980

The use of antibody and complement to gain access to the interior of presynaptic nerve terminals.

Treatment of synaptosomes with sera containing antibodies (Ab) directed against synaptosomal membranes and complement (C) alters the plasma membrane so that it becomes selectively permeable to small molecules and ions but not to proteins. When synaptosomes are incubated with Ab and C, a rapid release of intracellular K occurs. This release does not occur after treatment with antiserum alone, or with normal serum + C. Ab + C treatment releases approximately the same amount of K as does detergent treatment or hypotonic lysis, two procedures that extensively disrupt the plasma membrane. The selectivity of the complement-induced lesion is consistent with the equivalent pore radius determined in other systems (Michaels and Mayer 1978; Sears et al. 1964). The lesions are large enough to allow the rapid permeation of small ions, but too small to permit the escape of the soluble cytoplasmic enzyme, lactate dehydrogenase. In addition, electron microscopic studies indicate that Ab + C treatment does not lead to gross morphological disruption of the synaptosomes. Ab + C treated synaptosomes are also permeable to calcium and ATP, as demonstrated by the stimulation of Ca sequestration into endoplasmic reticulum when 45Ca and ATP are added to the incubation medium.

Adenosine Triphosphate↗
PubMed1993

Interactions of bilirubin with isolated presynaptic nerve terminals: functional effects on the uptake and release of neurotransmitters.

1. The functional effects of bilirubin:albumin solutions (10:1, mol/mol) on several synaptosomal functions were investigated using rat cortical, striatal, and hippocampal synaptosomes prepared by iso-osmotic Percoll/sucrose gradient centrifugation. 2. Bilirubin (10-80 microM) depolarized synaptosomes in a tetrodotoxin-insensitive manner as assessed by the equilibrium distribution of tetra-[3H]phenylphosphonium. Depolarization induced by bilirubin was of a lesser magnitude than that caused by KCl or veratridine. Steady-state pH gradients across the synaptosomal membrane were determined using the transmembrane distribution of [14C]methylamine. Bilirubin (20-40 microM) did not modify the intracellular pH in physiological buffers. The pigment effected a 0.14 delta pH change when the synaptosomes were suspended in a Ca2+ and Na+ free choline medium containing ouabain. 3. Bilirubin (20-80 microM) had no effect of its own on [7,8-3H] dopamine release from striatal synaptosomes. In contrast, it inhibited the initial rate of synaptosomal uptake of the catecholamine and its intrasynaptosomal content at 10 min. The pigment (20 and 40 microM) reduced the 35 mM KCl-induced release of endogenous acetylcholine from hippocampal synaptosomes by 20 and 36%, respectively. 4. The association of bilirubin with synaptic plasma membrane vesicles was characterized by a chloroform:methanol 2:1 (v/v) extraction method. At total concentrations of 10 to 80 microM bilirubin, the molar percentage of the pigment in synaptic plasma membrane phospholipids was 1-4%. 5. It is proposed that the two main functional consequences of the bilirubin-nerve ending interaction are an impairment of specific membrane-bound neurotransmitter uptake mechanisms and a reduction of the response to depolarizing stimuli. This may be the basis for rapid alterations in synaptic transmission documented in early reversible bilirubin encephalopathy.

Animals↗