Baclofen and Adenosine Inhibition of Synaptic Transmission at CA3-CA1 Synapses Display Differential Sensitivity to K+ Channel Blockade

The metabotropic GABA(B) and adenosine A(1) receptors mediate presynaptic inhibition through regulation of voltage-dependent Ca2+ channels, whereas K+ channel regulation is believed to have no role at the CA3-CA1 synapse. We show here that the inhibitory effect of baclofen (20 mu M) and adenosine (300 mu M) on field EPSPs are differentially sensitive to Cs+ (3.5 mM) and Ba2+ (200 mu M), but not 4-aminopyridine (100 mu M). Barium had no effect on paired-pulse facilitation (PPF) in itself, but gave significant reduction (14 +/- A 5%) when applied in the presence of baclofen, but not adenosine, suggesting that the effect is presynaptic and selective on the GABA(B) receptor-mediated response. The effect of Ba2+ on PPF was not mimicked by tertiapin (30 nM), indicating that the underlying mechanism does not involve GIRK channels. Barium did not affect PPF in slices from young rats (P7-P8), suggesting developmental regulation. The above effects of Ba2+ on adult tissue were reproduced when measuring evoked whole-cell EPSCs from CA1 pyramidal neurons: PPF was reduced by 22 +/- A 3% in the presence of baclofen and unaltered in adenosine. In contrast, Ba2+ caused no significant change in frequency or amplitude of miniature EPSCs. The Ba2+-induced reduction of PPF was antagonized by LY341495, suggesting metabotropic glutamate receptor involvement. We propose that these novel effects of Ba2+ and Cs+ are exerted through blockade of inwardly rectifying K+ channels in glial cells, which are functionally interacting with the GABA(B) receptor-dependent glutamate release that generates heterosynaptic depression.