The effects of excitatory amino acids and their antagonists on hippocampal electrophysiology
Creators: name: Kehl, Steven James
Publisher: name: University of British Columbia
Year: 2010

description: The role of excitatory acidic amino acids in synaptic transmission and the modulation of electrophysiological properties were examined in the hippocampal slice in vitro using conventional extracellular and intracellular recording techniques. Iontophoresis of L-glutamate, L-aspartate and the more potent and specific agonists N-methyl-DL-aspartate (NMA), kainate and quisqualate excited CA1 neurons; NMA was unique in causing cells to fire in bursts of repetitive discharges in contrast to the sustained firing observed with the other compounds. Iontophoretically-applied DL-2-amino-5-phosphonovalerate (APV) selectively blocked NMA excitations, an effect which was attributed to the D-isomer; ∂-D-glutamyl glycine (DGG) inhibited cell firing elicited by NMA, kainate and L-aspartate; at a higher dose it also inhibited responses to quisqualate and L-glutamate to some extent. L-glutamate diethyl ester, (+)-cis-2,3-piperidine dicarboxylate and DL-2-amino-4-phosphonobutyrate (APB) variously affected amino acid-mediated excitations but also had complicating secondary actions. The effects of iontophoresis to the stratum radiatum inCA1 of excitatory amino acids and some antagonists were evaluated on the field EPSP evoked by stimulation of the Schaffer collateral-commissural (SC) pathways. Each of the selective agonists as well as L-glutamate and L-aspartate depressed EPSPs. Kainate-induced depressions considerably outlasted the period of ejection whereas NMA depressions were rapidly reversible and often followed by an increased EPSP amplitude. APV abolished responses to NMA, did not change the EPSP but could block long term potentiation (LTP) of synaptic transmission. The optical isomers of APB had little or no effect of EPSPs. DGG was an effective synaptic antagonist whilst having no detectable effect on the presynaptic fibre volley. It is concluded that a kainate or quisqualate type receptor may be involved in Schaffer collateral-commissural--evoked synaptic transmission; NMA receptors may play a role in the neuronal processes underlying LTP. The interaction of L-glutamate and L-aspartate with these receptors is discussed. To determine the basis for its convulsant and neurotoxic properties the actions of kainate on synaptic processes were investigated. In CA1 and the dentate gyrus kainate produced a large and long-lasting increase of the orthodromic population spike (PS) and an associated decline of the EPSP; the amplitudes of presynaptic fibre volleys and antidromic PSs were unchanged. In the CA3 region lower doses of kainate potentiated synaptic excitations and epileptiform firing appeared spontaneously and following electrical stimulation. Kainate also reduced GABA-mediated inhibitions and IPSPs in CA1 and abolished in CA3 an inhibition which, on the basis of studies reported here appears to be non-GABAergic, but this disinhibitory action did not appear to underlie the increased excitability. Other excitatory amino acids could mimic only the depressant actions of higher doses of kainate. An increased coupling between dendrites and somata related perhaps to a dendritic depolarization is suggested as the basis for the potentiating action. The potentiating and disinhibitory properties of kainate are discussed in the context of its epileptogenicity and neurotoxicity. In CA1 and the dentate gyrus perfusion of folic acid, a possible endogenous activator of the kainic receptor, caused a potentiation of orthodromic PSs whilst the EPSP was either unaffected or depressed; antidromic responses were unchanged. In CA3 folate potentiated PSs and caused both spontaneous and evoked epileptiform discharges. Burst firing was Ca²⁺ dependent and was triggered by paroxysmal depolarization shifts indicating their synaptic origin. Unlike kainate, folate caused no measurable change of recurrent inhibition in CA1 and never directly depressed evoked activity. The implications of these data for folate neurotoxicity and the possible homologies of receptors for kainate and folate are discussed.