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PubMed1991

Dual mode of corticothalamic synaptic termination in the mediodorsal nucleus of the rhesus monkey.

Electron microscopic autoradiography (EM-ARG) was used to assess the synaptic organization of corticothalamic terminals in the parvicellular division of the mediodorsal thalamic nucleus. Examination of the synaptic organization in unreacted tissue revealed several distinct synaptic types distributed among glomerular and nonglomerular regions of the neuropil. Within glomeruli, three presynaptic terminal classes were found. The majority of profiles (as many as eight to ten per glomerulus) were presynaptic dendrites (PSDs) forming symmetric synaptic contacts with a central dendrite, and occasionally with other PSDs. One or two large terminals densely packed with round vesicles (LR terminals) were also present in each glomerulus. This terminal class made multiple asymmetric contacts with the central dendrite, as well as with many PSDs within the glomerulus. Finally, small terminals with round vesicles (SR terminals) formed asymmetric synaptic junctions with PSDs in some glomeruli. PSDs and SR terminals were also found in the extraglomerular neuropil, although in different proportions than in the glomeruli. In the extraglomerular neuropil SR terminals were the most abundant terminal class and these terminals made synaptic contacts with dendrites of all sizes. PSDs were seen in considerably smaller numbers than in the glomeruli. Finally, the extraglomerular neuropil contained a moderate number of small to medium terminals that formed symmetric synaptic junctions (SF terminals) with cell bodies and dendrites of all sizes. Synaptic profiles related to corticothalamic inputs were identified by injecting the prefrontal cortex of two rhesus monkeys with 3H-leucine and -proline and analyzing the distribution and morphology of radiolabeled terminals. Quantitative analysis of the density of silver grains over different tissue compartments revealed a positive labeling index for two terminal classes: SR and LR terminals. Labeled SR terminals were concentrated in the extraglomerular neuropil and labeled LR terminals were found within glomeruli where they formed synaptic contact with the central dendrite, as well as with presynaptic dendrites of the glomerulus. In contrast to many other thalamic nuclei, cortical input to the mediodorsal nucleus arrives via two distinctive synaptic pathways, one terminating extraglomerularly and the other terminating within the synaptic glomeruli. The dual mode of corticothalamic terminations in the mediodorsal nucleus suggests a more potent and possibly different role for cortical input in the regulation of neuronal activity in this association nucleus than in sensory nuclei of the thalamus.

Animals↗
PubMedDate not supplied

Neuronal compartments and axonal transport of synapsin I.

Studies on the transport kinetics and the posttranslational modification of synapsin I in mouse retinal ganglion cells were performed to obtain an insight into the possible factors involved in forming the structural and functional differences between the axon and its terminals. Synapsin I, a neuronal phosphoprotein associated with small synaptic vesicles and cytoskeletal elements at the presynaptic terminals, is thought to be involved in modulating neurotransmitter release. The state of phosphorylation of synapsin I in vitro regulates its interaction with both synaptic vesicles and cytoskeletal components, including microtubules and microfilaments. Here we present the first evidence that in the mouse retinal ganglion cells most synapsin I is transported down the axon, together with the cytomatrix proteins, at the same rate as the slow component b of axonal transport, and is phosphorylated at both the head and tail regions. In addition, our data suggest that, after synapsin I has reached the nerve endings, the relative proportions of variously phosphorylated synapsin I molecules change, and that these changes lead to a decrease in the overall content of phosphorus. These results are consistent with the hypothesis that, in vivo, the phosphorylation of synapsin I along the axon prevents the formation of a dense network that could impair organelle movement. On the other hand, the dephosphorylation of synapsin I at the nerve endings may regulate the clustering of small synaptic vesicles and modulate neurotransmitter release by controlling the availability of small synaptic vesicles for exocytosis.

Animals↗
PubMed1985

Transmission at voltage-clamped giant synapse of the squid: evidence for cooperativity of presynaptic calcium action.

Synaptic transmission was studied at the squid giant synapse with voltage clamp control of both presynaptic and postsynaptic cells. Because presynaptic voltage gradients can complicate interpretation of electrophysiological data obtained from this preparation, we used local Ca application to restrict Ca influx and transmitter release to a short and relatively isopotential portion of the elongated presynaptic terminal. Under these conditions, we found that postsynaptic current varies approximately as the third power of presynaptic Ca current. This finding is consistent with the hypothesis that several Ca ions cooperate in triggering secretion of a single transmitter quantum.

Animals↗
PubMed1994

Selective clustering of glutamate and gamma-aminobutyric acid receptors opposite terminals releasing the corresponding neurotransmitters.

Several immunocytochemical and physiological studies have demonstrated a concentration of neurotransmitter receptors at postsynaptic sites on neurons, but an overall picture of receptor distribution has not emerged. In particular, it has not been clear whether receptor clusters are selectively localized opposite terminals that release the corresponding neurotransmitter. By using antibodies against the excitatory glutamate receptor subunit GluR1 and the inhibitory type A gamma-aminobutyric acid (GABA) receptor beta 2/3 subunits, we show that these different receptor types cluster at distinct postsynaptic sites on cultured rat hippocampal neurons. The GABAA receptor beta 2/3 subunits clustered on cell bodies and dendritic shafts opposite GABAergic terminals, whereas GluR1 clustered mainly on dendritic spines and was associated with glutamatergic synapses. Chronic blockade of evoked transmitter release did not block receptor clustering at postsynaptic sites. These results suggest that complex mechanisms involving nerve terminal-specific signals are required to allow different postsynaptic receptor types to cluster opposite only appropriate presynaptic terminals.

Action Potentials↗
PubMedDate not supplied

Examination of the role of cGMP in long-term potentiation in the CA1 region of the hippocampus.

The mechanisms underlying the generation of NMDA receptor-dependent LTP in the CA1 region of the hippocampus continue to receive a great deal of attention because of the postulated importance of LTP as a synaptic mechanism for learning and memory. It is well accepted that the initial induction of LTP occurs in the postsynaptic cell, but the site of expression remains controversial. One prominent hypothesis is that LTP involves the release of one or more retrograde messengers that act on the presynaptic terminal to enhance transmitter release. Recently, evidence has been presented that retrograde messengers function to activate presynaptic guanylyl cyclase and that the resulting rise in presynaptic cGMP levels, when accompanied by presynaptic activity, is responsible for generating an early component of LTP. We have tested this hypothesis by examining whether synaptic strength is increased by coupling tetanic stimulation with application of a membrane-permeable analog of cGMP. The experiments were done in the presence of an NMDA receptor antagonist to block postsynaptic induction mechanisms. Under a variety of experimental conditions, this manipulation failed to generate LTP, suggesting that an increase in cGMP levels accompanied by presynaptic activity is not sufficient to generate LTP in the CA1 region of the hippocampus.

2-Amino-5-phosphonovalerate↗
PubMed2005

Progress from the postsynaptic side: signaling in synaptic differentiation.

The signals mediating synaptic differentiation are critical for our understanding of synapse formation and nervous system development. Recent progress highlights the roles of membrane-bound and soluble signaling pathways in this process. The postsynaptic adhesion molecules neuroligin-1, neuroligin-2, and SynCAM1 provide target-derived signals leading to the assembly of presynaptic terminals. In the reverse direction, neuroligins also relay signals into postsynaptic sites through interactions with their presynaptic partners, the beta-neurexins. This adhesion-based system helps to determine the neurotransmitter specificity of postsynaptic specializations. In addition, soluble molecules are released from target neurons and initiate presynaptic differentiation, as demonstrated for the fibroblast growth factor FGF-22. This Perspective summarizes new insights into early synaptic differentiation signals and discusses underlying principles.

Animals↗
PubMed2006

UNC-13 and UNC-10/rim localize synaptic vesicles to specific membrane domains.

Synaptic vesicles undergo a maturation step, termed priming, in which they become competent to fuse with the plasma membrane. To morphologically define the site of vesicle priming and identify fusion-competent synaptic vesicles, we combined a rapid physical-fixation technique with immunogold staining and high-resolution morphometric analysis at Caenorhabditis elegans neuromuscular junctions. In these presynaptic terminals, a subset of synaptic vesicles contact the plasma membrane within approximately 100 nm of a presynaptic dense projection. UNC-13, a protein required for vesicle priming, localizes to this same region of the plasma membrane. In an unc-13 null mutant, few synaptic vesicles contact the plasma membrane, suggesting that membrane-contacting synaptic vesicles represent the morphological correlates of primed vesicles. Interestingly, a subpopulation of membrane-contacting vesicles, located within 30 nm of a dense projection, are unperturbed in unc-13 mutants. We show that UNC-10/Rim, a protein implicated in presynaptic plasticity, localizes to dense projections and that loss of UNC-10/Rim causes an UNC-13-independent reduction in membrane-contacting synaptic vesicles within 30 nm of the dense projections. Our data together identify a discrete domain for vesicle priming within 100 nm of dense projections and further suggest that UNC-10/Rim and UNC-13 separately contribute to the membrane localization of synaptic vesicles within this domain.

Animals↗
PubMed1989

GABAergic neurons in the rat hippocampal formation: ultrastructure and synaptic relationships with catecholaminergic terminals.

Numerous studies indicate that gamma-aminobutyric acid (GABA) can either hyperpolarize or depolarize hippocampal pyramidal and granule cells. While the inhibitory action of GABA may occur directly on these cells, the excitatory action may be mediated by interactions of GABAergic neurons with each other or with catecholaminergic afferents. We sought to examine the cellular basis for these interactions and their relative frequency. Thus, the ultrastructural morphology of GABAergic neurons and their relation to terminals exhibiting immunoreactivity for the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) were examined in the rat hippocampal formation using combined immunoautoradiographic and peroxidase-antiperoxidase labeling methods. By light microscopy, GABAergic perikarya and processes codistributed most noticeably with TH-containing processes in the hilus of the dentate gyrus (DG) and in strata lucidum, radiatum, and lacunosum-moleculare of the CA3 region of the hippocampus. Thus, these regions were examined further by electron microscopy. In the ultrastructural analysis, GABA-like immunoreactivity (GABA-LI) was detected in neuronal perikarya, dendrites, axons, and axon terminals. The GABA-containing perikarya were large, ovoid (20-40 microns in diameter), and contained abundant cytoplasm and an indented nucleus with one nucleolus. Synaptic junctions on the perikarya and dendrites with GABA-LI were both symmetric and asymmetric. Approximately equal numbers of TH-labeled terminals (19% of 133 in DG; 39% of 26 in CA3) and GABA-containing terminals (19% DG, 15% CA3) formed synapses with GABA-labeled perikarya. The remainder of the presynaptic terminals (62% DG, 46% CA3) were unlabeled, i.e., contained unidentified transmitters. Terminals with GABA-LI (0.5-1.6 microns) contained numerous small clear vesicles and from 0 to 2 large dense-core vesicles. The types of associations formed by terminals with GABA-LI were remarkably similar in the DG and hippocampus proper despite differences in intrinsic cell type and function. Terminals with GABA-LI formed associations with unlabeled perikarya and dendrites (24% of 151 in DG, 25% of 75 in CA3) and synapses with GABA-containing perikarya and dendrites (18% DG, 5% CA3). Additionally, GABAergic terminals converged upon the same perikarya or dendrite as a TH-containing terminal (15% DG, 21% CA3) and were in direct apposition to TH-labeled terminals (19% DG, 20% CA3). The remaining GABAergic terminals (24% DG, 28% CA3) were without any apparent synaptic relations. In both the DG and CA3, the junctions formed by GABAergic terminals were symmetric. Terminals showing colocalization of GABA-LI and TH-I were also detected although rarely.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Dihydropyridine-sensitive calcium current mediates neurotransmitter release from bipolar cells of the goldfish retina.

The release of neurotransmitter is evoked by activation of the Ca current (ICa) at presynaptic terminals. Though multiple types of ICa have been reported in various cells, little is known about the properties of presynaptic ICa in the vertebrate CNS. The aim of this article is to identify the type of ICa involved in the release of neurotransmitter from retinal bipolar cells. Bipolar cells with a large axon terminal were isolated enzymatically from the goldfish retina, and studied by the following techniques: (1) recordings of ICa in the whole-cell recording configuration, (2) visualization of intracellular free Ca2+ concentration ([Ca2+]i) with the Fura-2 imaging system, and (3) real-time electrophysiological bioassay of released excitatory amino acid transmitter by a voltage-clamped horizontal cell isolated from the catfish retina. The only ICa found in bipolar cells was the high-voltage-activated, dihydropyridine-sensitive type. This result supports the recent study by Heidelberger and Matthews (1992). When ICa was activated by a short depolarizing pulse, a rapid increase of [Ca2+]i was restricted to the axon terminal. A much slower and smaller increase of [Ca2+]i was sometimes observed at the cell body, probably due to the diffusion of intracellular free Ca2+ from the axon terminal. The increase of [Ca2+]i was completely suppressed by nicardipine, suggesting that Ca2+ entered through dihydropyridine-sensitive Ca channels located mainly at the axon terminal. Activating ICa of the bipolar cell evoked a transmitter-induced current in the excitatory amino acid probe (i.e., the catfish horizontal cell). Both currents were suppressed concomitantly by nifedipine but not by omega-conotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Characterization of glycine transport in cultured Müller glial cells from the retina.

Rapid termination of the synaptic action of glutamate (Glu) and glycine (Gly) is achieved by uptake into the presynaptic terminal and glial cells. In the vertebrate CNS, Gly acts both as an inhibitory neurotransmitter and as a Glu modulator or coagonist at postsynaptic N-methyl-D-aspartate (NMDA) receptors. We have previously described NMDA receptors in Müller cells of chick retina coupled to the phosphoinositide cascade, the entry of calcium, and the activation of protein kinase C (PKC; López-Colomé et al. Glia 9:127-135, 1993). A colocalization of Gly transporters and NMDA receptors has been reported in brain tissue (Smith et al. Neuron 8:927-936, 1992); since the concentration of Gly could participate in the modulation of Glu excitatory transmission in the vertical pathways of the retina, transport of Gly in monolayer cultures of Müller cells was studied. Gly transport was found pH-sensitive with an optimum at pH 7.4. Kinetic analysis of the saturation curve for Gly within a concentration range of 0.01-2 mM, revealed two components of transport: a low-affinity system with Km = 1.7 mM, Vmax = 30 nmol/10 min/mg protein, and a high-affinity one with a Km = 27 microM, Vmax = 3 nmol/10 min/mg protein. Both systems were Na+ -dependent; the high-affinity system proved also dependent on external Cl- and was inhibited by sarcosine, characteristic of GLYT1 transporters. The inhibition of low-affinity uptake by 2-(methylamino)isobutyric acid (MeAIB) and 2-aminoisobutyric acid (AIB) suggests the presence of transport system A in Müller cells. The process is energy-requiring, since Gly transport was decreased by metabolic inhibitors. Data obtained are in keeping with a modulatory role for Müller glia on excitatory transmission in the retina.

2,4-Dinitrophenol↗
PubMed1986

Localization of alpha-spectrin in chicken and monkey ventral horns by immunoelectron microscopy.

Localization of alpha-spectrin in chicken and monkey ventral horns has been studied by immunoperoxidase techniques at the electron microscopic level. For this purpose, an antiserum specific for chicken alpha-spectrin (240 kD subunit of spectrin) was prepared. The characteristics of the staining patterns of both chicken and monkey ventral horns were essentially identical. The reaction product for peroxidase was contained in the somata of large cells (presumably motor neurons), dendrites and axons. No specific staining was seen with either preimmune or blocked sera. The staining within the cell somata was primarily localized in cortical cytoplasm. Within dendrites and axons the immunocytochemical label was associated predominantly with the cortical cytoplasm and with microtubules. Staining was heavy over postsynaptic densities. Although presynaptic terminals showed weak staining as a whole, heavy staining was sometimes observed in areas adjacent to the presynaptic plasma membrane facing the postsynaptic density. These results indicate that spectrin distributes widely and functions in many biological activities in the nervous system.

Animals↗
PubMed1976

Evidence that the rapid binding of newly accumulated noradrenaline within synaptosomes involves synaptic vesicles.

When rat brain synaptosomes were incubated with [3H]noradrenaline for 1 min and then exposed to osmotic shock, only about 20% of the newly accumulated [3H]noradrenaline was released. It would appear that most, but possibly not all of the newly accumulated [3H]noradrenaline is rapidly bound to some particulate cytoplasmic constituent within the synaptosome. [3H]Dopamine and [3H]5-hydroxytryptamine were also rapidly bound within synaptosomes but [3H]glycine and [3H]gamma-aminobutyric acid were not. Reserpinization (5 mg/kg, i.p., 24 h before preparation) only slightly reduced the initial rate of [3H]noradrenaline uptake by synaptosomes. However, when reserpinized synaptosomes were osmotically shocked, most of the newly accumulated radioactivity was released; this radioactivity was identified chromatographically as [3H]noradrenaline. On the basis of the findings with reserpinized preparations, it seems likely that (1) the rapid intrasynaptosomal binding involves synaptic vesicles and (2) the neuronal membrane transport system itself may be capable of driving the uptake of noradrenaline by nerve-terminals. The rapid vesicular binding observed may not be essential for the accumulation of the amine by presynaptic terminals during brief exposures.

Animals↗
PubMed1994

Combined fluid percussion brain injury and entorhinal cortical lesion: a model for assessing the interaction between neuroexcitation and deafferentation.

Laboratory studies suggest that excessive neuroexcitation and deafferentation contribute to long-term morbidity following human head injury. Because no current animal model of traumatic brain injury (TBI) has been shown to combine excessive neuroexcitation and significant levels of deafferentation, we developed a rat model combining the neuroexcitation of fluid percussion TBI with subsequent entorhinal cortical (EC) deafferentation. In this paradigm, moderate fluid percussion TBI was induced in each rat, followed 24 h later by bilateral EC lesion (BEC). Six conditions were examined: (1) fluid percussion TBI followed 24 h later by bilateral EC lesion (TBEC), (2) fluid percussion TBI (TBI), (3) bilateral EC lesion (BEC), (4) sham fluid percussion TBI (SHAM), (5) TBI followed 24 h later by unilateral EC lesion (TUEC), and (6) unilateral EC lesion (UEC). The first four groups were assessed for motor (with beam-balance and beam-walk testing) and cognitive deficits (with the Morris water maze) and hippocampal morphology (with immunocytochemistry and electron microscopy). The TUEC and UEC groups were assessed for cognitive deficits alone. Motor deficits were greater in the TBEC injury than in TBI or sham alone; however, no significant difference was observed between the TBEC and BEC conditions in motor performance. Cognitive deficits were of a greater magnitude in the combined TBEC injury model relative to each individual insult. These cognitive deficits appeared to be additive for the two experimental injuries, BEC deafferentation producing deficits intermediate between TBI and TBEC insults. Morphologic analysis of the dentate gyrus molecular layer at 15 days after TBEC showed that the distribution of synaptophysin-positive presynaptic terminals was distinct from that observed after either TBI or BEC alone. Specifically, the laminar pattern of presynaptic rearrangement induced by BEC lesion did not occur after TBEC injury. The present results show that axonal injury and its attendant deafferentation, when coupled with traumatically induced neuroexcitation, produce an enhancement of the morbidity associated with TBI. Moreover, they indicate that this model can effectively be used to study the interaction between neuroexcitation and synaptic plasticity.

Animals↗
PubMedDate not supplied

Complete cerebral ischaemia in the rat: an ultrastructural and stereological analysis of the distal stratum radiatum in the hippocampal CA-1 region.

An ultrastructural study and a stereological analysis of the distal stratum radiatum in the hippocampal CA-1 region of the rat were performed after 10 min of complete cerebral ischaemia followed by 10, 20 and 60 min of blood reflow periods. Post-ischaemic changes were mainly limited to the region of synaptic terminals which showed either clumping or dispersion of the synaptic vesicle pools and damage to synaptic membranes. Presynaptic terminals and astrocytes were swollen after 10 and 20 min of reflow, but this abated after 60 min. Mitochondria in neurons showed varying degrees of swelling, but in astrocytes their structure was normal. There were no changes in capillaries. After 20 and 60 min of blood reflow, disruption of cell membranes was observed, mainly in the vicinity of the synaptic terminals. The size of the extracellular space diminished by approximately 30% in all three ischaemic groups. The data show that synaptic terminals are a primary and early target in the development of postischaemic nerve cell damage.

Animals↗
PubMed1996

Reliability of spike propagation in arborizations of dorsal root fibers studied by analysis of postsynaptic potentials mediated by electrotonic coupling in the frog spinal cord.

1. Postsynaptic potentials were recorded in lumbar motoneurons of the frog in response to electrical activation of dorsal roots. After chemical synaptic transmission was blocked by replacing Ca2+ with Mg2+ in the superfusion medium, it was confirmed that the remaining electrical excitatory postsynaptic potentials (EEPSPs) recorded in motoneurons consisted of potential changes-produced by electrical coupling between the motoneurons and the stimulated axons. The EEPSPs could then be used as an assay to study the reliability of spike propagation into presynaptic terminals. 2. EEPSPs typically consisted of three components. The first was a small positive deflection (prespike or presynaptic volley) that could also be recorded extracellularly. The second component was a spikelike fast positive component and the third was a slow positive component that followed the second but had a distinct maximum and a slow decay. The amplitude of the fast component did not correlate with that of either the prespike or the slow component. 3. 4-Aminopyridine (0.1 mM), which widens action potentials by blocking K+ channels, increased the amplitude and width of EEPSPs. Heptanol (1-4 mM), which is known to be a blocker of electrical coupling, could block EEPSPs. 4. The amplitudes of EEPSPs evoked by dorsal root stimulation were compared at different temperatures (7.5-19.5 degrees C). A slight decrease of the amplitude of the fast component with increasing temperature (Q10 = 0.8) was within limits predicted by resistance-capacitance filtering of the presynaptic spike at the different temperatures, suggesting that the temperature does not affect propagation of the spike in this synapse. 5. The amplitude of the fast component of EEPSPs evoked by single-pulse and paired-pulse stimulation did not fluctuate more than the baseline noise in 37 experiments in which the SD of baseline noise was < 100 microV. We conclude that electrical synaptic transmission does not fluctuate intermittently in this system, and that branch points conduct or fail to conduct for periods of time longer than the longest period in the analyzed experiments.

Animals↗
PubMed2000

Interaction of the C-terminal tail region of the metabotropic glutamate receptor 7 with the protein kinase C substrate PICK1.

Group III metabotropic glutamate receptors (mGluRs) are highly enriched in the presynaptic terminals of glutamatergic synapses where they mediate feedback inhibition of neurotransmitter release. Here, we used the yeast two-hybrid system to identify a direct interaction of the C-terminal tail region of mGluR7 with the rat homologue of the protein kinase C substrate PICK1. This interaction is specifically mediated by the very C-terminal amino acids of the receptor and can be reconstituted in human embryonic kidney 293 cells by transfection of full-length mGluR7 and PICK1 cDNAs. Quantitative beta-galactosidase assays revealed that among the different group III mGluRs, mGluR7 is the major PICK1 binding partner although other subfamily members can also interact with PICK1. These data indicate that PDZ domain-containing proteins might contribute to the presynaptic localization of group III mGluRs.

Amino Acid Sequence↗
PubMedDate not supplied

Actions of endomorphins on synaptic transmission of Adelta-fibers in spinal cord dorsal horn neurons.

The effects of endogenous mu-opioid ligands, endomorphins, on Adelta-afferent-evoked excitatory postsynaptic currents (EPSCs) were studied in substantia gelatinosa neurons in spinal cord slices. Under voltage-clamp conditions, endomorphins blocked the evoked EPSCs in a dose-dependent manner. To determine if the block resulted from changes in transmitter release from glutamatergic synaptic terminals, the opioid actions on miniature excitatory postsynaptic currents (mEPSCs) were examined. Endomorphins (1 microM) reduced the frequency but not the amplitude of mEPSCs, suggesting that endomorphins directly act on presynaptic terminals. The effects of endomorphins on the unitary (quantal) properties of the evoked EPSCs were also studied. Endomorphins reduced unitary content without significantly changing unitary amplitude. These results suggest that in addition to presynaptic actions on interneurons, endomorphins also inhibit evoked EPSCs by reducing transmitter release from Adelta-afferent terminals.

2-Amino-5-phosphonovalerate↗
PubMed2003

Localization of the O-GlcNAc transferase and O-GlcNAc-modified proteins in rat cerebellar cortex.

O-linked N-acetylglucosamine (O-GlcNAc) is a ubiquitous nucleocytoplasmic protein modification that has a complex interplay with phosphorylation on cytoskeletal proteins, signaling proteins and transcription factors. O-GlcNAc is essential for life at the single cell level, and much indirect evidence suggests it plays an important role in nerve cell biology and neurodegenerative disease. Here we show the localization of O-GlcNAc Transferase (OGTase) mRNA, OGTase protein, and O-GlcNAc-modified proteins in the rat cerebellar cortex. The sites of OGTase mRNA expression were determined by in situ hybridization histochemistry. Intense hybridization signals were present in neurons, especially in the Purkinje cells. Fluorescent-tagged antibody against OGTase stained almost all of the neurons with especially intense reactivity in Purkinje cells, within which the nucleus, perikaryon, and dendrites were most intensely stained. Using immuno-electron microscopic labeling, OGTase was seen to be enriched in euchromatin, in the cytoplasmic matrix, at the nerve terminal, and around microtubules in dendrites. In nerve terminals, immuno-gold labeling was observed around synaptic vesicles, with the enzyme more densely localized in the presynaptic terminals than in the postsynaptic ones. Using an antibody to O-GlcNAc, we found the sugar localizations reflected results seen for OGTase. Collectively, these data support hypothesized roles for O-GlcNAc in key processes of brain cells, including the regulation of transcription, synaptic vesicle secretion, transport, and signal transduction. Thus, by modulating the phosphorylation or protein associations of key regulatory and cytoskeletal proteins, O-GlcNAc is likely important to many functions of the cerebellum.

Acetylglucosamine↗