The Cholinergic Status differentially alters GABAergic Inhibition in Neocortex

Abstract

This thesis study was designed to investigate the impact of the neuromodulator acetylcholine (ACh) on γ-aminobutyric acid (GABA)-ergic inhibition in neocortex. GABAergic inhibition counterbalances excitatory transmission by glutamatergic pyramidal cells (PY), the dominating neuronal cell type in cortex. Inhibition is provided by a diversity of interneuron (IN) classes which differ in terms of morphology, electrophysiological properties and sensitivity to ACh. Importantly, IN classes establish postsynaptic connections characterized by specific subtype composition of the GABAA receptors (GABAAR). Thus, the principal hypothesis investigated here is that ACh should modulate the quality and possibly the magnitude of GABAergic inhibition in neocortex by altering the relative inhibitory impact of different GABAAR subtypes. This hypothesis was investigated on the basis of subtype-specific GABAAR pharmacology and targeted recordings of somatostatin-positive (SOM+) INs in mostly spontaneously active in vitro preparations of neocortex. Congruent with expectations, ACh excited SOM+ INs and increased inhibition in the network, as evident in a higher frequency of inhibitory postsynaptic potentials (IPSCs) recorded in voltage-clamp experiments and shorter and smaller spontaneous network bursts in extracellular recordings in organotypic cultures of neocortex. To investigate the involvement of specific GABAAR subunits, GABAAR modulators with differing subunit preferences were tested in the presence and absence of ACh. Results revealed that the actions of GABAAR modulators on burst parameters and correlation of activity were specifically altered by the presence of ACh. Overall, inhibition and decorrelation increased most when the α1, 2, 3 modulator zolpidem was applied in the presence of ACh, while the additional modulation of GABAARs containing the α5 subunit with diazepam suspended the differences between the two ACh conditions. The functional antagonism of α5 subunit-containing GABAAR by L-655,708 evoked a difference between the two ACh conditions opposite to the differences seen with zolpidem. Thus, the α5 subunit is proposed to play an important role in ACh-induced inhibition.