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Long-Term Regulation of Neuronal High-Affinity Glutamate and Glutamine Uptake in Aplysia

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Long-Term Regulation of Neuronal High-Affinity Glutamate and Glutamine Uptake in Aplysia Long-term regulation of neuronal high-affinity glutamate and glutamine uptake in Aplysia Jonathan Levenson*, Shogo Endo*†, Lorna S. Kategaya*, Raymond I. Fernandez*, David G. Brabham*, Jeannie Chin‡, John H. Byrne‡, and Arnold Eskin*§ *University of Houston, Department of Biology and Biochemistry, 4800 Calhoun Road, Houston, TX 77204-5513; and ‡Department of Neurobiology and Anatomy, University of Texas, Houston Medical School, Houston, TX 77225 Edited by Eric R. Kandel, Columbia University, New York, NY, and approved August 22, 2000 (received for review June 5, 2000) An increase in transmitter release accompanying long-term sensi- Beach, CA). They were maintained at 15°C under 12-h light/12-h tization and facilitation occurs at the glutamatergic sensorimotor dark and fed every 2–3 days. Animals were in the lab for 3 days synapse of Aplysia. We report that a long-term increase in neuronal before use. Experiments investigating duration of siphon with- Glu uptake also accompanies long-term sensitization. Synapto- drawal after long-term sensitization training or exposure to somes from pleural-pedal ganglia exhibited sodium-dependent, 5-hydroxytryptamine (5-HT; serotonin) in vivo were performed high-affinity Glu transport. Different treatments that induce long- as described (6, 11). term enhancement of the siphon-withdrawal reflex, or long-term Uptake was measured by using a synaptosomal preparation synaptic facilitation increased Glu uptake. Moreover, 5-hydroxy- tryptamine, a treatment that induces long-term facilitation, also derived from pleural-pedal ganglia as described (Fig. 3A; ref. 29). produced a long-term increase in Glu uptake in cultures of sensory Animals were anesthetized with an injection of isotonic MgCl2. neurons. The mechanism for the increase in uptake is an increase Pleural-pedal ganglia were removed and trimmed of excess in the Vmax of transport. The long-term increase in Glu uptake connective tissue. Synaptosomes were immediately prepared as appeared to be dependent on mRNA and protein synthesis, and the uptake activity declined with time of ganglia in culture. Each transport through the Golgi, because 5,6-dichlorobenzimidazole experiment involved synaptosomes from 8–10 ganglia. In exper- ϩ ϩ ϩ riboside, emetine, and brefeldin A inhibited the increase in Glu iments on Na dependency of uptake, the Na of the Ca2 -free ͞ ͞ ͞ uptake. Also, injection of emetine and 5,6-dichlorobenzimidazole seawater [460 mM NaCl 10 mM KCl 55 mM MgCl2 20 mM into Aplysia prevented long-term sensitization. Synthesis of Glu Tris⅐HCl (pH 7.4)͞0.1% glucose] was completely replaced with itself may be regulated during long-term sensitization because the N-methyl-D-glucamine (Sigma). same treatments that produced an increase in Glu uptake also Uptake was determined by incubation of 15–30 ␮g of synap- produced a parallel increase in Gln uptake. These results suggest tosomal protein for 20 min in Glu ([U-14C], Ն250 mCi͞mmol, that coordinated regulation of a number of different processes ICN), Gln ([U-14C], Ն200 mCi͞mmol, NEN) or Leu ([2,3,4,5- may be required to establish or maintain long-term synaptic 3H], Ն110 Ci͞mmol, ICN). Experiments were terminated by facilitation. ϩ dilution of the synaptosomes with 10 volumes of ice-cold Ca2 - free seawater. Synaptosomes were then centrifuged (16,000 ϫ g) he sensorimotor synapse of Aplysia has proven particularly for 5 min. The pellet was rinsed three times with 4°C Ca2ϩ-free Tuseful for the study of the cellular and molecular mechanisms seawater and dissolved directly in scintillation fluid to determine of long-term facilitation as well as several other types of neural total Glu uptake. Uptake was normalized to total protein. plasticity (1–3). Thus far, several neuronal properties have been The enrichment of synaptosomes was verified via immunoblot implicated in long-term memory, including modulation of mem- of synaptophysin, a nerve terminal protein (30), and Ag, a glial brane currents, regulation of transmitter release, and changes in morphology (4–11). All of these long-term changes are depen- protein (31). Whole fractions and their pellets were solubilized in 1% SDS and diluted in a 3X loading dye (Bio-Rad). Proteins dent on both transcription and translation (5, 12, 13). Given that ͞ transmitter release is increased during long-term facilitation, were separated by 12% SDS PAGE, transferred to a poly(vi- one question that arises is whether other long-term presynaptic nylidene difluoride) (Bio-Rad) membrane, blocked with 5% dry changes such as transmitter uptake and synthesis are coordinated milk (Carnation, Glendale, CA), and blotted with either a mAb with increased transmitter release. against synaptophysin (SY38, 0.7 ␮g͞ml, Boehringer Mannheim) An increasing body of evidence indicates that the excitatory or an affinity-purified polyclonal antiserum against Ag (fraction transmitter of the sensorimotor synapse is Glu (14–19). Glu 4, 1:5,000, a gift from I. Levitan, University of Pennsylvania, transporters are poised to impact synaptic efficacy significantly Philadelphia). Immunoreactivity was visualized with a chemilu- because the uptake of transmitter represents a major mechanism minescent detection system (enhanced chemiluminescence, Am- whereby neurotransmission is terminated and neurotransmitter ersham International). The horseradish peroxidase-conjugated is recycled (20–22). Inhibiting basal Glu uptake affects the secondary antibodies used (Jackson ImmunoResearch, 1:20,000) amplitude and duration of postsynaptic potentials and currents were donkey anti-mouse (Synaptophysin) or donkey anti-rabbit at a number of different synapses including the sensorimotor (Ag). synapse of Aplysia (19, 23–27). In addition, blockade of Glu uptake immediately after aversive training blocks the expression of long-term memory in the newborn chick (28). These findings This paper was submitted directly (Track II) to the PNAS office. demonstrate that Glu uptake is important for normal synaptic Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); DRB, 5,6-dichlorobenzimidazole function and suggest Glu uptake may be involved in expression riboside; THA, DL-threo-␤-hydroxyaspartate. of plasticity at glutamatergic synapses. Thus, we hypothesized †Present address: Laboratory for Learning and Memory, RIKEN, Brain Science Institute, that the increased release of transmitter at the sensorimotor Waco, Japan 351-0198. synapse during facilitation is accompanied by an increase in Glu §To whom reprint requests should be addressed. E-mail: [email protected]. uptake. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Materials and Methods §1734 solely to indicate this fact. Aplysia californica (100–150 g) were obtained from Marinus Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073͞pnas.220256497. (Long Beach, CA) and Alacrity Marine Biological (Redondo Article and publication date are at www.pnas.org͞cgi͞doi͞10.1073͞pnas.220256497 12858–12863 ͉ PNAS ͉ November 7, 2000 ͉ vol. 97 ͉ no. 23 Downloaded by guest on September 23, 2021 Ag is a secreted glial protein in Aplysia (31). To ensure that the immunoblotted Ag was contained within glia or glial fragments, all fractions were exposed to proteinase K [Sigma; 0.125 mg͞ml ͞ ͞ in artificial seawater: 395 mM NaCl 28 mM Na2SO4 10 mM ͞ ͞ ͞ ⅐ KCl 50 mM MgCl2 10 mM CaCl2 10 mM Tris HCl (pH 8)] to eliminate extracellular protein. The synaptosomal fractions were diluted with an equal volume of proteinase K solution, and incubated at 20°C for 0.5 h. The reaction was then incubated at 4°C for 15 min with PMSF (5 mM, Sigma) to inactivate pro- teinase K. Uptake of Glu by synaptosomes was characterized with Glu uptake inhibitors: DL-threo-␤-hydroxyaspartate (THA, Sigma), pyrrolidine-dicarboxylic acid (Research Biochemicals, Natick, MA), and aminocyclobutane-dicarboxylic acid (Sigma). All drugs were dissolved in 1 N NaOH to a final concentration of: 134 mM THA͞628 mM pyrrolidine-dicarboxylic acid͞251 mM aminocyclobutane-dicarboxylic acid. Final solutions were made by adding the drug solution and an equal volume of 1 N HCl to Ca2ϩ-free seawater in which the salt concentrations and pH were modified to compensate for the addition of the volume of drug Fig. 1. Synaptosomes exhibit high-affinity Glu uptake. Glu uptake was measured in synaptosomal preparations (P3; see Fig. 3A) derived from pleural- solution. pedal ganglia. Synaptosomal Glu uptake was measured from control (solid Glu uptake was measured in sensory neurons cultured as line, F) and experimental (500 ␮M 5-HT, dashed line, {) animals 24 h after described (32, 33) at a density of 20–70 neurons per dish. treatment. Glu uptake by synaptosomes was dose dependent. Note the ap- Neurons were allowed to grow for 5 days before use in a medium parent increase in Vmax from synaptosomes isolated 24 h after treatment of consisting of equal parts isotonic L-15 and hemolymph. To animals with 5-HT. (Inset) Lineweaver–Burk analysis of data in main graph. measure uptake, the medium was replaced with artificial sea- Each experiment contained synaptosomes derived from 8–10 pleural-pedal ͞ ͞ ͞ ganglia. In this and subsequent illustrations, error bars are SEM. water [395 mM NaCl 28 mM Na2SO4 10 mM KCl 50 mM ͞ ͞ MgCl2 10 mM CaCl2 30 mM Hepes (pH 7.65)]. After rinsing with artificial seawater, cultures were incubated in 2 ml of 10 ␮M [14C]Glu at 15°C for 30 min. Uptake was terminated by rinsing Several reasons may account for the difference in IC50s for THA in 4°C seawater. Excess solution was quickly removed with a measured in synaptosomes and whole ganglia. The connective KimWipe, and cells and their processes were lifted from the tissue sheath of the ganglia may present a diffusional barrier. In culture plate with scintillation fluid. Glu uptake was normalized addition, Glu uptake by whole ganglia is via two different to the number of sensory neurons on the culture dish.
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