title: Roles of the NMDA Receptor and EAAC1 Transporter in the Modulation of Extracellular Glutamate by Low and High Affinity AMPA Receptors in the Cerebellum in Vivo: Differential Alteration in Chronic Hyperammonemia.
abstract: The roles of high- and low-affinity AMPA receptors in modulating extracellular glutamate in the cerebellum remain unclear. Altered glutamatergic neurotransmission is involved in neurological alterations in hyperammonemia, which differently affects high- and low-affinity AMPA receptors. The aims were to assess by in vivo microdialysis (a) the effects of high- and low-affinity AMPA receptor activation on extracellular glutamate in the cerebellum; (b) whether chronic hyperammonemia alters extracellular glutamate modulation by high- and/or low-affinity AMPA receptors; and (c) the contribution of NMDA receptors and EAAC1 transporter to AMPA-induced changes in extracellular glutamate. In control rats, high affinity receptor activation does not affect extracellular glutamate but increases glutamate if NMDA receptors are blocked. Low affinity AMPA receptor activation increases transiently extracellular glutamate followed by reduction below basal levels and return to basal values. The reduction is associated with transient increased membrane expression of EAAC1 and is prevented by blocking NMDA receptors. Blocking NMDA receptors with MK-801 induces a transient increase in extracellular glutamate which is associated with reduced membrane expression of EAAC1 followed by increased membrane expression of the glutamate transporter GLT-1. Chronic hyperammonemia does not affect responses to activation of low affinity AMPA receptors. Activation of high affinity AMPA receptors increases extracellular glutamate in hyperammonemic rats by an NMDA receptor-dependent mechanism. In conclusion, these results show that there is a tightly controlled interplay between AMPA and NMDA receptors and an EAAC1 transporter in controlling extracellular glutamate. Hyperammonemia alters high- but not low-affinity AMPA receptors.
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe , Calle Eduardo Primo Yufera, 3, 46012 Valencia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cabrera-Pastor
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe , Calle Eduardo Primo Yufera, 3, 46012 Valencia, Spain.
authors.forename: Lucas
authors.initials: L
authors.lastname: Taoro
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe , Calle Eduardo Primo Yufera, 3, 46012 Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Llansola
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe , Calle Eduardo Primo Yufera, 3, 46012 Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D022124:Hyperammonemia / Q000473:pathology*; D008297:Male; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C493398:Slc1a1 protein, rat; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
keywords: AMPA receptors; EAAC1 glutamate transporter; NMDA receptors; extracellular glutamate; glutamate uptake; hyperammonemia