Evidence for endogenous excitatory amino acids as mediators in DSI of GABA(A)ergic transmission in hippocampal CA1.
Depolarization-induced suppression of inhibition (DSI) is a process whereby brief approximately 1-s depolarization to the postsynaptic membrane of hippocampal CA1 pyramidal cells results in a transient suppression of GABA(A)ergic synaptic transmission. DSI is triggered by a postsynaptic rise in [Ca(2+)](in) and yet is expressed presynaptically, which implies that a retrograde signal is involved. Recent evidence based on synthetic metabotropic glutamate receptor (mGluR) agonists and antagonists suggested that group I mGluRs take part in the expression of DSI and raised the possibility that glutamate or a glutamate-like substance is the retrograde messenger in hippocampal CA1. This hypothesis was tested, and it was found that the endogenous amino acids L-glutamate (L-Glu) and L-cysteine sulfinic acid (L-CSA) suppressed GABA(A)-receptor-mediated inhibitory postsynaptic currents (IPSCs) and occluded DSI, whereas L-homocysteic acid (L-HCA) and L-homocysteine sulfinic acid (L-HCSA) did not. Activation of metabotropic kainate receptors with kainic acid (KA) reduced IPSCs; however, DSI was not occluded. When iontophoretically applied, both L-Glu and L-CSA produced a transient IPSC suppression similar in magnitude and time course to that observed during DSI. Both DSI and the actions of the amino acids were antagonized by (S)-alpha-methyl-4-carboxyphenylglycine ([S]-MCPG), indicating that the effects of the endogenous agonists were produced through activation of mGluRs. Blocking excitatory amino acid transport significantly increased DSI and the suppression produced by L-Glu or L-CSA without affecting the time constant of recovery from the suppression. Similar to DSI, IPSC suppression by L-Glu or L-CSA was blocked by N-ethylmaleimide (NEM). Moreover, paired-pulse depression (PPD), which is unaltered during DSI, is also not significantly affected by the amino acids. Taken together, these results support the glutamate hypothesis of DSI and argue that L-Glu or L-CSA are potential retrograde messengers in CA1.
Morishita
W
W
Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Alger
B E
BE
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D018846:Excitatory Amino Acids / Q000494:pharmacology* / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
D018846:Excitatory Amino Acids; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D006710:Homocysteine; C007956:homocysteic acid; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D003545:Cysteine; C013461:cysteine sulfinic acid