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

Abstract

The metabotropic GABA_B and adenosine A₁ 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 μM) and adenosine (300 μM) on field EPSPs are differentially sensitive to Cs⁺ (3.5 mM) and Ba²⁺ (200 μM), but not 4-aminopyridine (100 μM). Barium had no effect on paired-pulse facilitation (PPF) in itself, but gave significant reduction (14 ± 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 ± 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.