Tonic GABAA Conductance Favors Spike-Timing-Dependent over Theta-Burst-Induced Long-Term Potentiation in the Hippocampus.

Abstract

Synaptic plasticity is triggered by different patterns of network activity. Here, we investigated how LTP in CA3-CA1 synapses induced by different stimulation patterns is affected by tonic GABAA conductances in rat hippocampal slices. Spike-timing-dependent LTP was induced by pairing Schaffer collateral stimulation with antidromic stimulation of CA1 pyramidal neurons. Theta-burst-induced LTP was induced by theta-burst stimulation of Schaffer collaterals. We mimicked increased tonic GABAA conductance by bath application of 30 μm GABA. Surprisingly, tonic GABAA conductance selectively suppressed theta-burst-induced LTP but not spike-timing-dependent LTP. We combined whole-cell patch-clamp electrophysiology, two-photon Ca2+ imaging, glutamate uncaging, and mathematical modeling to dissect the mechanisms underlying these differential effects of tonic GABAA conductance. We found that Ca2+ transients during pairing of an action potential with an EPSP were less sensitive to tonic GABAA conductance-induced shunting inhibition than Ca2+ transients induced by EPSP burst. Our results may explain how different forms of memory are affected by increasing tonic GABAA conductances under physiological or pathologic conditions, as well as under the influence of substances that target extrasynaptic GABAA receptors (e.g., neurosteroids, sedatives, antiepileptic drugs, and alcohol).SIGNIFICANCE STATEMENT Brain activity is associated with neuronal firing and synaptic signaling among neurons. Synaptic plasticity represents a mechanism for learning and memory. However, some neurotransmitters that escape the synaptic cleft or are released by astrocytes can target extrasynaptic receptors. Extrasynaptic GABAA receptors mediate tonic conductances that reduce the excitability of neurons by shunting. This results in the decreased ability for neurons to fire action potentials, but when action potentials are successfully triggered, tonic conductances are unable to reduce them significantly. As such, tonic GABAA conductances have minimal effects on spike-timing-dependent synaptic plasticity while strongly attenuating the plasticity evoked by EPSP bursts. Our findings shed light on how changes in tonic conductances can selectively affect different forms of learning and memory.