Evidence for endogenous excitatory amino acids as mediators in DSI of GABAAergic transmission in hippocampal CA1

Evidence for endogenous excitatory amino acids as mediators in DSI of GABA(A)ergic transmission in hippocampal CA1. J. Neurophysiol. 82: 2556-2564, 1999. Depolarization-induced suppression of inhibition (DSI) is a process whereby brief similar to 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 [Ca2+](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 CAI. 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-carboxyyphenylglycine ([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.