Adenosine A1 Receptor-Mediated Presynaptic Inhibition of GABAergic Transmission in Immature Rat Hippocampal CA1 Neurons

Abstract

In the mechanically dissociated rat hippocampal CA1 neurons with native presynaptic nerve endings, namely “synaptic bouton” preparation, the purinergic modulation of spontaneous GABAergic miniature inhibitory postsynaptic currents (mIPSCs) was investigated using whole-cell recording mode under the voltage-clamp conditions. In immature neurons, adenosine (10 μM) reversibly decreased GABAergic mIPSC frequency without affecting the mean current amplitude. The inhibitory effect of adenosine transmission was completely blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM), a selective Α1 receptor antagonist, and was mimicked by N 6-cyclopentyladenosine (CPA, 1 μM), a selective Α1 receptor agonist. However, CPA had no effect on GABAergic mIPSC frequency in postnatal 30 day neurons. N-ethylmaleimide (10 μM), a guanosine 5′-triphosphate binding protein uncoupler, and Ca2+-free external solution removed the CPA-induced inhibition of mIPSC frequency. K+ channel blockers, 4-aminopyridine (100 μM) and Ba2+ (1 mM), had no effect on the inhibitory effect of CPA on GABAergic mIPSC frequency. Stimulation of adenylyl cyclase with forskolin (10 μM) prevented the CPA action on GABAergic mIPSC frequency. Rp-cAMPS (100 μM), a selective PKA inhibitor, also blocked the CPA action. It was concluded that the activation of presynaptic Α1 receptors modulates the probability of spontaneous GABA release via cAMP- and protein kinase A dependent pathway. This Α1 receptor-mediated modulation of GABAergic transmission may play an important role in the regulation of excitability of immature hippocampal CA1 neurons.