A role for presynaptic AMPA receptors in the enhancement of neuronal glutamate release by kainic acid.

Abstract

Kainic acid (KA), an analogue of glutamic acid, is a powerful neuroexcitant and neurotoxin. It has been proposed that an increased release of excitatory amino acids (EAAs) from synaptic terminals substantially contributes to the central neurotoxic action of this compound [1,2]. We have recently reported the existence of presynaptic, cyclothiazide (CYZ)-sensitive AMPA receptors on glutamatergic nerve terminals in rat forebrain slices [3]. These receptors appear to mediate a positive feedback control on synaptic glutamate release. We now report that these novel autoreceptors may play a role in KA-mediated enhancement of neuronal glutamate release. Serial rat forebrain coronal sections were cut and loaded with [3H]D-aspaxtate (PHID-asp) as previously described [4]. Following loading with PHID-asp, slices were superfused with oxygenated Krebs buffer and the influence of agonists and antagonists on basal and electrically stimulated (36mA, 2msec pulses, 20Hz for 5min) release of label was examined using a standard protocol [4]. Electrically stimulated release in this preparation is calcium-dependent and tetrodotoxin-insensitive, confirming that it arises principally from direct stimulation of presynaptic nerve terminals [ 5 ] . The results are summarized in Figure 1 and Table 1. KA (1-1selectively enhanced elecmcally-stimulated efflux of [3H]D-asp with a bell-shaped dose-response curve (max. 2.7 fold enhancement at 10 pM). Basal efflux of label was not significantly increased. In the presence of a low (1OpM) concentration of the AMPA receptor desensitization inhibitor CYZ, responses to KA, 1-100pM remained u~changed, wheieas responses to KA, ImM were markedly potentiated (approx. 4.2 fold enhancement). Consistent with this, the selective AMPA receptor antagonists NBQX [13] and GYKI 52466 114,151 (1100pM) failed to influence responses to KA, 100pM plus CYZ,