Mossy fibers (MF), the axons of granule cells in the hippocampus dentate gyrus, which in adulthood are glutamatergic, in the immediate postnatal period release GABA (Safiulina et al., 2006). Here we show that presynaptic kainate receptors (KARs) localized on MF terminals exert a powerful inhibition on GABA release. GABA-A mediated postsynaptic currents (GPSCs) evoked by minimal stimulation of granule cells in the dentate gyrus were recorded from CA3 pyramidal cells using the patch clamp technique (whole cell in voltage clamp configuration). Bath application of AMPA receptor antagonist 4-(8-Methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride (GYKI, 30 mM) did not modify the amplitude or the kinetics of GPSCs. Addition of the GluK1 KAR antagonist, (S)-1-(2-Amino-2-carboxylethyl)-3-(2-carboxylbenzyl)pyrimidine-2,4-dione (UBP 302, 10 mM) to GYKI, significantly increased the amplitude of GPSCs from 48.2 ± 8.2 pA to 83.7 ± 14.8 pA (n = 19; P<0.001). In contrast, the GluK1 KAR agonist (RS)-2-Amino-3-(3-hydroxy-5-tert-butylioxazol-4-yl)propanoic acid (ATPA, 1 mM), significantly reduced GPSC amplitude from 54.3 pA ± 9.3 pA to 21.8 ± 3.7 pA (n = 11; P<0.01), indicating that GluK1 KAR are involved in modulation of GABA release. These receptors were activated by glutamate present on the extracellular space as demonstrated by the observation that the enzymatic glutamate scavenger system (glutamic-pyruvic transminase [GPT] + pyruvate) was able to mimic the effect of UBP 302. Pertussis toxin, which inhibits G proteins, fully prevented the potentiating action of UBP 302, suggesting that GluK1 KAR has a metabotropic function. This effect was on presynaptically localized KARs because using GDPbs into the patch pipette failed to block the effects of UBP 302. Furthermore, both ATPA and UBP 302 decreased and increased the probability of antidromic firing in granule cells (recorded in current clamp conditions), respectively.

These data strongly indicate that presynaptic GluK1 KARs, activated by ambient glutamate play a crucial role in regulating GABA release from MF terminals, an effect that involves a metabotropic type of KA receptor.

Safiulina VF, Fattorini G, Conti F & Cherubini E (2006) GABAergic signaling at mossy fiber synapses in neonatal rat hippocampus. J Neurosci. 26:597–608.