title: Effects of 3-aminoglutarate, a "silent" false transmitter for glutamate neurons, on synaptic transmission and epileptiform activity.
abstract: Pharmacological tools that interact with the mechanisms that regulate vesicular filling and release of the neurotransmitter L-glutamate would be of enormous value. In this study, we provide physiological evidence that the glutamate analog, 3-aminoglutarate (3-AG), acts as a false transmitter to reduce presynaptic glutamate release. 3-AG inhibits glutamate-mediated neurotransmission both in primary neuronal cultures and in brain slices with more intact neural circuits. When assayed with the low affinity glutamate receptor antagonist γ-DGG, we demonstrate that 3-AG significantly reduces the synaptic cleft glutamate concentration, suggesting that 3-AG may act as a false transmitter to compete with glutamate during vesicle filling. Furthermore, using three different epileptic models (Mg(2+)-free, 4-AP, and high K(+)), we demonstrate that 3-AG is capable of suppressing epileptiform activity both before and after its induction. Our studies, along with those of the companion paper by Foster et al. (2015) indicate that 3-AG is a "silent" false transmitter for glutamate neurons that is a useful pharmacological tool to probe the mechanisms governing vesicular storage and release of glutamate under both physiological and pathophysiological conditions. 3-AG may have potential therapeutic value in conditions where the glutamate neurotransmitter system is pathologically overactive.
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Biological Sciences, Allergan Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.affiliation: Department of Biological Sciences, Allergan Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Staubli
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Chicheng
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Biological Sciences, Allergan Inc., 2525 Dupont Drive, Irvine, CA 92612, USA. Electronic address: li_yongxin@allergan.com.
authors.forename: Yong-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: gongchen@psu.edu.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D000927:Anticonvulsants; D005971:Glutamates; D018377:Neurotransmitter Agents; D017470:Receptors, Glutamate; C035260:3-aminoglutaric acid; D018698:Glutamic Acid
keywords: Epilepsy; False transmitter; Glutamate; Synaptic transmission; Synaptic vesicle; Transmitter release