Probing the polarity of spontaneous GABAergic synaptic transmission in vivo

Several studies suggest a contribution of reversed, excitatory GABA to epileptogenesis. But GABAergic transmission critically depends on the very dynamic combination of membrane potential, conductance and occurrence of other synaptic inputs. Taking this complexity into account implies measuring the postsynaptic responses to spontaneously occurring GABAergic events, in vivo, without interfering with neuronal [Cl-]i. Because of technical difficulties, this has not been achieved yet. We have overcome this challenge by combining in vivo extracellular detection of both optogenetically-evoked and spontaneously occurring unitary inhibitory postsynaptic field-potentials (fIPSPs), with the silicon probe recording of neuronal firing activity, with single cell resolution. We report that isolated acute seizures induced a global reversal of the polarity of CA3 hippocampal GABAergic transmission, shifting from inhibitory to excitatory for a duration of several tens of seconds before returning to normal polarity. Nevertheless we observed this reversed polarity only in the post-ictal period during which neurons (including GABAergic interneurons) were silent. Perisomatic inhibition was also affected during the course of epileptogenesis in the Kainate model of chronic epilepsy. One week after Kainate injection, the majority of pyramidal cells escaped inhibitory control by perisomatic GABAergic events. Besides, we did not observe a reversed polarity of fIPSPs, but fIPSPs provided time-locked excitation to a minor subset of CA3 pyramidal neurons. Beside methodological interests, our results suggest that subtle alterations in the regulation of [Cl-]i and perisomatic GABAergic transmission already operate in the hippocampal circuit during the latent period that precedes the establishment of chronic epilepsy.