title: Synaptic plasticity in glutamatergic and GABAergic neurotransmission following chronic memantine treatment in an in vitro model of limbic epileptogenesis.
abstract: Chronic N-methyl-D-aspartate receptor (NMDAR) blockade with high affinity competitive and uncompetitive antagonists can lead to seizure exacerbation, presumably due to an imbalance in glutamatergic and GABAergic transmission. Acute administration of the moderate affinity NMDAR antagonist memantine in vivo has been associated with pro- and anticonvulsive properties. Chronic treatment with memantine can exacerbate seizures. Therefore, we hypothesized that chronic memantine treatment would increase glutamatergic and decrease GABAergic transmission, similar to high affinity competitive and uncompetitive antagonists. To test this hypothesis, organotypic hippocampal slice culture were treated for 17-21 days with memantine and then subjected to electrophysiological recordings. Whole-cell recordings from dentate granule cells revealed that chronic memantine treatment slightly, but significantly increased sEPSC frequency, mEPSC amplitude and mEPSC charge transfer, consistent with minimally increased glutamatergic transmission. Chronic memantine treatment also increased both sIPSC and mIPSC frequency and amplitude, suggestive of increased GABAergic transmission. Results suggest that a simple imbalance between glutamatergic and GABAergic neurotransmission may not underlie memantine's ictogenic properties. That said, glutamatergic and GABAergic transmission were assayed independently of one another in the current study. More complex interactions between glutamatergic and GABAergic transmission may prevail under conditions of intact circuitry.
authors.affiliation: Graduate Program in Neuroscience, Uniformed Services University, School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Shuijin
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pharmacology, Uniformed Services University, School of Medicine, Bethesda, MD 20814, USA; Graduate Program in Neuroscience, Uniformed Services University, School of Medicine, Bethesda, MD 20814, USA. Electronic address: suzanne.bausch@usuhs.edu.
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Bausch
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D008559:Memantine
keywords: 6-cyano-7-nitroquinoxaline-2,3-dione; BMI; CNQX; D(−)-2-amino-5-phosphonopentanoic acid; D-APV; Dentate granule cell; Electrophysiology; GABA; Hippocampus; N-methyl-d-aspartate receptors; NMDAR; PSC; RMP; Resting membrane potential; SEM; Slice culture; TTX; aCSF; artificial cerebrospinal fluid; bicuculline methiodide; large amplitude spontaneous excitatory postsynaptic current; mEPSC; mIPSC; miniature excitatory postsynaptic current; miniature inhibitory postsynaptic current; postsynaptic current; resting membrane potential; sEPSC; sEPSC(large); sEPSC(small); sIPSC; small amplitude spontaneous excitatory postsynaptic current; spontaneous excitatory postsynaptic current; spontaneous inhibitory postsynaptic current; standard error of the mean; tetrodotoxin; γ-aminobutyric acid