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At least 883 records · Page 49Linked to original sources
PubMed2003

Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating.

We describe the isolation and characterization of Drosophila synaptojanin (synj) mutants. synj encodes a phosphatidylinositol phosphatase involved in clathrin-mediated endocytosis. We show that Synj is specifically localized to presynaptic terminals and is associated with synaptic vesicles. The electrophysiological and ultrastructural defects observed in synj mutants are strikingly similar to those found in endophilin mutants, and Synj and Endo colocalize and interact biochemically. Moreover, synj; endo double mutant synaptic terminals exhibit properties that are very similar to terminals of each single mutant, and overexpression of Endophilin can partially rescue the functional defects in partial loss-of-function synj mutants. Interestingly, Synj is mislocalized and destabilized at synapses devoid of Endophilin, suggesting that Endophilin recruits and stabilizes Synj on newly formed vesicles to promote vesicle uncoating. Our data also provide further evidence that kiss-and-run is able to maintain neurotransmitter release when synapses are not extensively challenged.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release.

Evoked transmitter release depends upon calcium influx into synaptic boutons, but mechanisms regulating bouton calcium levels and spontaneous transmitter release are obscure. To understand these processes better, we monitored calcium transients in axons and presynaptic terminals of pyramidal neurons in hippocampal slice cultures. Action potentials reliably evoke calcium transients in axons and boutons. Calcium-induced calcium release (CICR) from internal stores contributes to the transients in boutons and to paired-pulse facilitation of EPSPs. Store depletion activates store-operated calcium channels, influencing the frequency of spontaneous transmitter release. Boutons display spontaneous Ca2+ transients; blocking CICR reduces the frequency of these transients and of spontaneous miniature synaptic events. Thus, spontaneous transmitter release is largely calcium mediated, driven by Ca2+ release from internal stores. Bouton store release is important for short-term synaptic plasticity and may also contribute to long-term plasticity.

Action Potentials↗
PubMed2001

Hippocampal synaptic transmission and plasticity are preserved in myosin Va mutant mice.

Recent studies have identified myosin Va as an organelle motor that may have important functions in neurons. Abundantly expressed at the hippocampal postsynaptic density, it interacts with protein complexes involved in synaptic plasticity. It is also located in presynaptic terminals and may function to recruit vesicles in the reserve pool to the active zone. Dilute-lethal mice are spontaneous myosin Va mutants and have severe neurological symptoms. We studied hippocampal physiology at CA3-CA1 excitatory synapses in dilute-lethal mutant mice to test the hypothesis that myosin Va plays a role in pre- or postsynaptic elements of synaptic transmission. In all assays performed, the mutant synapses appeared to be functioning normally, both pre- and postsynaptically. These data suggest that myosin Va is not essential for the synaptic release machinery, postsynaptic receptor composition, or plasticity at this synapse, but does not exclude significant roles for myosin Va in other cell types nor potential compensation by other myosin V isoforms.

Animals↗
PubMed1999

Synapsins as regulators of neurotransmitter release.

One of the crucial issues in understanding neuronal transmission is to define the role(s) of the numerous proteins that are localized within presynaptic terminals and are thought to participate in the regulation of the synaptic vesicle life cycle. Synapsins are a multigene family of neuron-specific phosphoproteins and are the most abundant proteins on synaptic vesicles. Synapsins are able to interact in vitro with lipid and protein components of synaptic vesicles and with various cytoskeletal proteins, including actin. These and other studies have led to a model in which synapsins, by tethering synaptic vesicles to each other and to an actin-based cytoskeletal meshwork, maintain a reserve pool of vesicles in the vicinity of the active zone. Perturbation of synapsin function in a variety of preparations led to a selective disruption of this reserve pool and to an increase in synaptic depression, suggesting that the synapsin-dependent cluster of vesicles is required to sustain release of neurotransmitter in response to high levels of neuronal activity. In a recent study performed at the squid giant synapse, perturbation of synapsin function resulted in a selective disruption of the reserve pool of vesicles and in addition, led to an inhibition and slowing of the kinetics of neurotransmitter release, indicating a second role for synapsins downstream from vesicle docking. These data suggest that synapsins are involved in two distinct reactions which are crucial for exocytosis in presynaptic nerve terminals. This review describes our current understanding of the molecular mechanisms by which synapsins modulate synaptic transmission, while the increasingly well-documented role of the synapsins in synapse formation and stabilization lies beyond the scope of this review.

Animals↗
PubMed2002

Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis.

The mu 2 subunit of the AP2 complex is known to be phosphorylated in vitro by a copurifying kinase, and it has been demonstrated recently that mu 2 phosphorylation is required for transferrin endocytosis (Olusanya, O., P.D. Andrews, J.R. Swedlow, and E. Smythe. 2001. Curr. Biol. 11:896-900). However, the identity of the endogenous kinase responsible for this phosphorylation is unknown. Here we identify and characterize a novel member of the Prk/Ark family of serine/threonine kinases, adaptor-associated kinase (AAK)1. We find that AAK1 copurifies with adaptor protein (AP)2 and that it directly binds the ear domain of alpha-adaptin in vivo and in vitro. In neuronal cells, AAK1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and AP2 in clathrin-coated pits and at the leading edge of migrating cells. AAK1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by AAK1 results in a decrease in AP2-stimulated transferrin internalization. Together, these results provide strong evidence that AAK1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis. These results also lend support to the idea that clathrin-mediated endocytosis is controlled by cycles of phosphorylation/desphosphorylation.

Adaptor Protein Complex 2↗
PubMed2002

Inhibition of glutamatergic synaptic input to spinal lamina II(o) neurons by presynaptic alpha(2)-adrenergic receptors.

Activation of spinal alpha(2)-adrenergic receptors by the descending noradrenergic system and alpha(2)-adrenergic agonists produces analgesia. However, the sites and mechanisms of the analgesic action of spinally administered alpha(2)-adrenergic receptor agonists such as clonidine are not fully known. The dorsal horn neurons in the outer zone of lamina II (lamina II(o)) are important for processing nociceptive information from C-fiber primary afferents. In the present study, we tested a hypothesis that activation of presynaptic alpha(2)-adrenergic receptors by clonidine inhibits the excitatory synaptic input to lamina II(o) neurons. Whole cell voltage-clamp recordings were performed on visualized lamina II(o) neurons in the spinal cord slice of rats. The miniature excitatory postsynaptic currents (mEPSCs) were recorded in the presence of tetrodotoxin, bicuculline, and strychnine. The evoked EPSCs were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Both mEPSCs and evoked EPSCs were abolished by application of 6-cyano-7-nitroquinoxaline-2,3-dione. Clonidine (10 microM) significantly decreased the frequency of mEPSCs from 5.8 +/- 0.9 to 2.7 +/- 0.6 Hz (means +/- SE) without altering the amplitude and the decay time constant of mEPSCs in 25 of 27 lamina II(o) neurons. Yohimbine (2 microM, an alpha(2)-adrenergic receptor antagonist), but not prazosin (2 microM, an alpha(1)-adrenergic receptor antagonist), blocked the inhibitory effect of clonidine on the mEPSCs. Clonidine (1-20 microM, n = 8) also significantly attenuated the peak amplitude of evoked EPSCs in a concentration-dependent manner. The effect of clonidine on evoked EPSCs was abolished in the presence of yohimbine (n = 5). These data suggest that clonidine inhibits the excitatory synaptic input to lamina II(o) neurons through activation of alpha(2)-adrenergic receptors located on the glutamatergic afferent terminals. Presynaptic inhibition of glutamate release from primary afferents onto lamina II(o) neurons likely plays an important role in the analgesic action produced by activation of the descending noradrenergic system and alpha(2)-adrenergic agonists.

Adrenergic alpha-Agonists↗
PubMed1999

Arachidonic acid as a messenger for the expression of long-term potentiation.

Arachidonic acid is suggested to play a role in the expression of long-term potentiation (LTP), a synaptic analog of memory and learning. However, it is unknown whether this free fatty acid is actually released during LTP or not. To address this question, we assayed arachidonic acid with an HPLC system using 9-anthryldiazomethane (ADAM) as a fluorescent probe. High frequency stimulation (tetanic stimulation) to a hippocampal slice from the guinea pig brain caused a huge increase in the release of glutamate from presynaptic terminals and in turn, a gradual increase in the release of arachidonic acid. A similar increase in the release of arachidonic acid was induced by application of glutamate and the increase was inhibited by either the selective AMPA/kainate receptor antagonist, DNQX, or to a lesser extent by the selective NMDA receptor antagonist, APV. These findings suggest that arachidonic acid is produced by activation of ionotropic glutamate receptors involving expression of LTP. Arachidonic acid exerted a long-lasting facilitatory action on synaptic transmission in the CA1 region of rat hippocampal slices and the facilitation occluded the tetanic LTP. Arachidonic acid, thus, appears to be a significant factor for the expression of LTP.

2-Amino-5-phosphonovalerate↗
PubMed1994

Quantitative three-dimensional confocal microscopy of synaptic structures in living brain tissue.

In order to study changes in synaptic structure that accompany learning and memory, we have developed optical methods to visualize dendritic spines and presynaptic terminals in living, electrically monitored brain slices maintained in vitro. Focal microapplication of the fluorescent lipophilic dye DiI provides Golgi-like staining of small numbers of cells and processes that can be resolved clearly using confocal microscopy; viability of stained cells is established by exclusion of the fluorescent DNA-binding dye ethidium bromide. Serial optical sections are enhanced by deconvolution and other image processing methods. The resulting high-resolution images are combined in an automated procedure to generate three-dimensional reconstructions, in which submicron synaptic structures can be viewed and measured. These unbiased methods allow volume changes in individual, living synaptic structures to be assessed quantitatively over periods of hours or days in development or in response to stimulation, drug application, or other perturbations.

Animals↗
PubMed2005

Activation of glutamate receptors promotes a calcium-dependent and transporter-mediated release of purines in cultured avian retinal cells: possible involvement of calcium/calmodulin-dependent protein kinase II.

Calcium-dependent release of purines was previously demonstrated in cultures of chick retinal cells stimulated with high potassium concentrations but there is no evidence for an exocytotic mechanism of adenosine release from presynaptic terminals. Here we show that activation of NMDA or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate glutamate ionotropic receptors promotes a two- to three-fold increase in the release of purines from these cultures. Approximately 96% of intracellular radioactivity is found as nucleotides after incubation with [(3)H]adenosine, but more than 85% of glutamate-stimulated released material is found as inosine (60%), hypoxanthine (19.9%) and adenosine (7.8%). The release is prevented by removal of extracellular calcium, by the transporter blocker nitrobenzylthioinosine, or inhibitors of calcium/calmodulin-dependent protein kinase II (CAMK II). The uptake of [(3)H]adenosine, but not of [(3)H]GABA or [(3)H]choline, is also blocked by 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine (KN62), N-[2-(N-(4-chlorocinnamyl)-N-methylaminomethyl)phenyl-N-[2-hydroxiethyl]-4-methoxybenzenesulfonamide (KN93) or the myristoylated autocamtide-2-related inhibitory peptide, suggesting that the enzyme modulates the nucleoside transporter. The distribution of intracellular purines was not affected by KN62. These results indicate that activation of glutamate receptors triggers the release of purines from retinal cells by a mechanism involving calcium influx, CAMK II and the nitrobenzylthioinosine-sensitive nucleoside transporter. The regulation of adenosine release by glutamate receptors and CAMK II could have important consequences in the presynaptic control of glutamate release.

Adenosine↗
PubMed2004

Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity.

The plasticity of synapses within neural circuits is regulated by activity, but the underlying mechanisms remain elusive. Using the dye FM1-43 to directly image presynaptic function, we found that large numbers of presynaptic terminals in hippocampal cultures have a low release probability. While these terminals were not readily modifiable, a transient but not permanent long-term reduction of network activity or Ca2+ influx could increase their modifiability. This modulation of plasticity was mediated by Ca2+ flux through NMDA and voltage-gated calcium channels and was lost within 48 hr. A more permanent enhancement of synaptic plasticity was achieved by selectively reducing the Ca2+ flux associated with uncorrelated activity via adjustment of the voltage-dependent Mg2+ block of the NMDAR. Upregulation of NR2B-containing NMDARs induced by this treatment is an important but not sole contributor to the enhancement of plasticity. Thus, quantity and quality of activity have differential effects on the intrinsic plasticity of neurons.

Animals↗
PubMed2006

Neurotrophin 3 induces structural and functional modification of synapses through distinct molecular mechanisms.

The mechanisms by which neurotrophins elicit long-term structural and functional changes of synapses are not known. We report the mechanistic separation of functional and structural synaptic regulation by neurotrophin 3 (NT-3), using the neuromuscular synapse as a model. Inhibition of cAMP response element (CRE)-binding protein (CREB)-mediated transcription blocks the enhancement of transmitter release elicited by NT-3, without affecting the synaptic varicosity of the presynaptic terminals. Further analysis indicates that CREB is activated through Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) pathway, rather than the mitogen-activated protein kinase (MAPK) or cAMP pathway. In contrast, inhibition of MAPK prevents the NT-3-induced structural, but not functional, changes. Genetic and imaging experiments indicate that the small GTPase Rap1, but not Ras, acts upstream of MAPK activation by NT-3. Thus, NT-3 initiates parallel structural and functional modifications of synapses through the Rap1-MAPK and CaMKIV-CREB pathways, respectively. These findings may have implications in the general mechanisms of long-term synaptic modulation by neurotrophins.

Animals↗
PubMed2005

Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion.

Neurotransmitter release is triggered by an increase in the cytosolic Ca2+ concentration ([Ca2+]i), but it is unknown whether the Ca2+-sensitivity of vesicle fusion is modulated during synaptic plasticity. We investigated whether the potentiation of neurotransmitter release by phorbol esters, which target presynaptic protein kinase C (PKC)/munc-13 signalling cascades, exerts a direct effect on the Ca2+-sensitivity of vesicle fusion. Using direct presynaptic Ca2+-manipulation and Ca2+ uncaging at a giant presynaptic terminal, the calyx of Held, we show that phorbol esters potentiate transmitter release by increasing the apparent Ca2+-sensitivity of vesicle fusion. Phorbol esters potentiate Ca2+-evoked release as well as the spontaneous release rate. We explain both effects by an increased fusion 'willingness' in a new allosteric model of Ca2+-activation of vesicle fusion. In agreement with an allosteric mechanism, we observe that the classically high Ca2+ cooperativity in triggering vesicle fusion (approximately 4) is gradually reduced below 3 microM [Ca2+]i, reaching a value of <1 at basal [Ca2+]i. Our data indicate that spontaneous transmitter release close to resting [Ca2+]i is a consequence of an intrinsic property of the molecular machinery that mediates synaptic vesicle fusion.

Allosteric Regulation↗
PubMed2006

Neurotrophic factors acutely alter the sorting of the vesicular acetyl choline transporter and the vesicular monoamine transporter 2 in bimodal sympathetic neurons.

Individual sympathetic neurons in co-cultures with cardiac myocytes store acetylcholine and noradrenaline in two different populations of synaptic vesicles and release both neurotransmitters from single presynaptic terminals. Neurotrophic factors selectively and acutely stimulate differential release of the two types of neurotransmitters from these bimodal neurons. Here we investigated the acute effects of neurotrophic factors on two pivotal marker proteins for catecholaminergic and cholinergic synaptic vesicle populations: the vesicular monoamine transporter 2 and the vesicular acetylcholine transporter. We observed that separation of the two fluorescence labeled transporters is not restricted to the varicosities, but can also be observed in the neurites as well as in the cell soma. Application of nerve growth factor, brain-derived neurotrophic factor and ciliary neuronotrophic factor caused acute alterations in transporter segregation. These results point to a novel function of neurotrophic factors during the short-term regulation of synaptic protein sorting in neurons.

Acetylcholine↗
PubMed1999

Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration.

Apolipoprotein (apo) E isoforms are key determinants of susceptibility to Alzheimer's disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.

Aging↗
PubMed1996

Presynaptic muscarinic cholinergic receptors in the dorsal hippocampus regulate behavioral inhibition of preweanling rats.

The aim of this research was to determine whether early maturation of the dorsal hippocampal cholinergic system mediates behavior exhibited by preweanling rats in the presence or absence of an unfamiliar adult male rat, a threatening stimulus. The behavioral responses that were examined included behavioral inhibition or freezing which emerges at 2 weeks of age and ultrasonic vocalizations. Prior to behavioral testing, oxotremorine, an M2 muscarinic receptor agonist that reduces cholinergic release from presynaptic terminals, was infused into the dorsal hippocampal dentate gyrus. Results demonstrated that 14-day-old rats with bilateral hippocampal infusions of a 1 microgram dose of oxotremorine exhibited significant deficits in freezing when exposed to the adult male rat. Importantly, oxotremorine had no significant effects on ultrasound emission and ambulatory activity when rat pups were tested in social isolation. Thus, effects of oxotremorine in the hippocampal dentate gyrus do not produce global changes in behavior. Results suggest that cholinergic release into the dorsal hippocampus facilitates the display of behavioral inhibition at the end of the second postnatal week. Behavioral deficits in freezing may reflect an oxotremorine-induced disruption of hippocampal cholinergic function underlying the processing of biologically relevant olfactory stimuli as well as mechanisms associated with attention.

Analysis of Variance↗
PubMed2002

Subcellular distribution of high-voltage-activated calcium channel subtypes in rat globus pallidus neurons.

Globus pallidus (GP) neurons receive dense inhibitory synaptic inputs interspersed with sparse excitatory inputs distributed across the entire extent of their somata and dendrites. Yet, despite this predominance of inhibitory influence, GP neurons fire at a high tonic rate, suggesting that intrinsic properties play an important role in determining the physiological characteristics of these neurons. High-voltage-activated (HVA) calcium channels represent an important class of conductances that plays roles in controlling neurotransmitter release, postsynaptic excitability, and intracellular calcium signaling. To better understand the intrinsic properties of GP neurons, we examined the subcellular localization of HVA calcium channels by using immunocytochemistry at the electron microscopic level. Peroxidase labeling with antibodies against P/Q-, N-, and R-type HVA calcium channels demonstrated the presence of these channels in both proximal and distal dendrites of GP neurons. P/Q-, N-, and R-type channels were also found in presynaptic terminals, whereas L-type channels were found exclusively postsynaptically in neuronal elements. Immunogold labeling demonstrated that, although the density of intracellular L-type calcium channel labeling remains constant throughout the proximal-distal extent of the dendritic tree of GP neurons, the density of plasma membrane-bound channels is greater in distal dendrites. The finding of HVA calcium channels distributed throughout the whole dendritic tree of GP neurons indicates that these channels may interact with synaptic inputs to allow rich processing possibilities for GP neuron dendrites. Furthermore, the finding of a greater density of plasma membrane-bound L-type channels in distal dendrites expands the view that L-type channels are important only in somatic and proximal locations.

Animals↗
PubMed1994

Stimulation of postsynaptic and inhibition of presynaptic adenylyl cyclase activity by metabotropic glutamate receptor activation.

To determine the subcellular distribution of cyclic AMP-coupled metabotropic glutamate receptors (mGluRs), the effects of glutamate agonists on adenylyl cyclase activity were examined using two hippocampal membrane preparations. These were synaptosomes (SY), which are composed of presynaptic terminals, and synaptoneurosomes (SN), which are composed of both pre- and postsynaptic elements. In SY, a water-soluble analogue of forskolin (7 beta-forskolin) increased enzyme activity approximately 10-fold at the highest concentration tested. The selective metabotropic receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) inhibited enzyme activity as did glutamate and quisqualate. L-Amino-4-phosphobutanoate (L-AP4) had no effect on enzyme activity at any concentration tested. The metabotropic receptor antagonist L-2-amino-3-phosphopropionic acid (L-AP3) was not effective in the SY in antagonizing the agonist-induced decreases in adenylyl cyclase activity by glutamate or 1S,3R-ACPD. It was, however, effective at antagonizing quisqualate-induced decreases in enzyme activity. In SN, at the highest concentration tested, 7 beta-forskolin produced a 60-fold increase in adenylyl cyclase activity. As was observed in SY, glutamate decreased adenylyl cyclase activity in SN. In contrast, 1S,3R-ACPD, quisqualate, and L-AP4 increased adenylyl cyclase activity. In the SN, L-AP3 was ineffective in antagonizing any agonist-induced increases (1S,3R-ACPD, L-AP4, and quisqualate) or decreases (glutamate) in adenylyl cyclase activity. The data suggest that postsynaptic metabotropic glutamate receptor activation results in stimulation of adenylyl cyclase activity, whereas inhibition of this enzyme appears to be mediated at least partly through presynaptic mechanisms.

Adenylyl Cyclase Inhibitors↗
PubMed2002

Synaptic depression improves coincidence detection in the nucleus laminaris in brainstem slices of the chick embryo.

Neurons in the nucleus laminaris detect the coincidence of binaural signals, and are the first neurons to calculate the interaural time difference for the sound source localization in birds. In this paper, we have studied contributions of synaptic depression to the coincidence detection in the nucleus laminaris in a slice preparation of the chick embryo (E16-18), using the whole-cell patch recording technique. Under voltage clamp, EPSCs decreased progressively in their amplitude during the course of tetanic stimuli. This synaptic depression was primarily ascribed to the reduction of transmitter release from the presynaptic terminal, because the depression was decreased by reducing transmitter release with 2.5 microm Cd2+ but was not affected by reducing desensitization of postsynaptic AMPA receptors with 20 microm cyclothiazide. Under current clamp, trains of 10 stimuli of 100 Hz were applied bilaterally with changing the time intervals systematically between both sides. Response window, defined as the time interval corresponding to the half-maximum firing probability, was narrowed during the course of the stimulus train, and this occurred in parallel with a decrease in the EPSP amplitude. In addition, the reduction of the EPSP amplitude due to 2.5 microm Cd2+ or 2 microm CNQX improved the accuracy of coincidence detection. These results indicate that the synaptic depression may improve the coincidence detection in the chick laminaris neurons.

Action Potentials↗