Dual GABAA receptor-mediated inhibition in rat presympathetic paraventricular nucleus neurons

The inhibitory neurotransmitter GABA plays a key role in the modulation of paraventricular nucleus (PVN) neuronal excitability and sympathoexcitatory outflow, under both physiological and pathological conditions. In addition to mediating conventional synaptic transmission (phasic inhibition), GABA(A) receptors of distinct biophysical, molecular and pharmacological properties have been recently found to underlie a slower, persistent form of inhibition (tonic inhibition). Whether the 'tonic' inhibitory modality is present in presympathetic PVN neurons, and what its role is in modulating their activity is at present unknown. Here, we combined tract-tracing techniques with patch-clamp electrophysiology to address these questions. Recordings obtained from PVN-RVLM (rostral ventrolateral medulla) projecting neurons show that besides blocking GABA(A)-mediated inhibitory postsynaptic currents (IPSCs, I-phasic), the GABA(A) receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (I-tonic). Conversely, the high affinity GABA(A) blocker gabazine blocked I-phasic without affecting I-tonic. THIP, a GABA(A) receptor agonist that preferentially activates delta- over gamma-containing receptors, enhanced the magnitude of I-tonic. Our results also indicate that during conditions of strong and/or synchronous synaptic activity, I-tonic may be activated by spillover of synaptically released GABA. Blockade of I-tonic induced membrane depolarization, increased firing activity, and enhanced the input-output function of PVN-RVLM neurons. Altogether, our results support the presence of a persistent GABA(A)-mediated inhibitory modality in presympathetic PVN neurons, which plays a major role in modulating their excitability and firing activity.