Experimental Anaesthesiology Antkowiak Lab:Processing
Sektion für Experimentelle Anaesthesiologie - Kortikale Informationsverarbeitung
Cholinergic modulation of GABAergic inhibition in neocortex
Acetylcholine (ACh), a neuromodulator vital to vigilance and cognition, is classically associated with an 'activating' or excitatory function in neocortex. However, ACh excites not only glutamatergic neurons, but also certain classes of inhibitory interneurons. The project is aimed at elucidating in which manner the cholinergic status of cortical networks alters GABAergic inhibition.
We start from the working hypothesis that interneurons sensitive to ACh activate GABA(A) receptors with a subunit composition and pharmacological profile different from that of receptors postsynaptic to ACh-insensitive interneurons. Furthermore, presynaptic modulation of GABA release by ACh may depend on interneuron type. Therefore, the degree of cholinergic activation should govern the contribution of different interneuron types and GABA(A) receptor subtypes to inhibition in cortical networks in multiple ways. We pursue this idea by comparing population activity patterns, inhibitory currents and activity profiles of interneurons in cortical networks in vitro subjected to different conditions of cholinergic stimulation and blockade.
Funded by DFG (HE 6210/1-1)
Enhancing spillover of GABA to peri- und extrasynaptic GABA(A) receptors – a possible route to anesthesia?
GABA is the major inhibitory transmitter in the mammalian central nervous system. At synaptic terminals of GABAergic neurons it reaches peak concentrations in the millimolar range, activating synaptic GABA(A) receptors. After release, GABA is very efficiently taken up by GABA transporters (GAT). These membrane-bound transporters, particularly GAT-1, are localized close to the synaptic release sites of GABA. The transporters' activity both curtails the duration of the GABA pulses in the synaptic cleft and restrains spillover of GABA out of the synaptic cleft.
In the light of this pivotal function of GAT we hypothesize that impeding their uptake capacity should have strong inhibitory effects on cortical networks. Specifically, inhibition of GAT-1 very likely enhances the concentration and the dwell time of GABA molecules in and around the synaptic cleft. This enhanced prevalence of GABA should activate (or enhance activation of) GABA(A) receptors which experience subsaturating concentrations of GABA. Most likely, these are peri- and extrasynaptic receptors, which are far away from the sites of GABA release. Depending on the degree of saturation of the synaptic receptors under normal conditions, these may also benefit from a more sluggish removal of GABA.
We probe these hypotheses by exposing spontaneously active cortical networks in vitro to inhibitors of GAT, and by assessing the changes in GABA(A) receptor-mediated currents and activity patterns.