Insulin promotes GABA signalling modulation in both the mouse hippocampus and human CD4+ T cells

Gamma-aminobutyric acid (GABA) is the most common inhibitory neurotransmitter in the adult mammalian brain, where it mediates several biological functions. Rapid inhibition is predominantly mediated by the activation of GABA-A receptors that are ubiquitously expressed across the central nervous system in a cell-, circuit-, or region-specific manner. This work contains four studies where GABA signalling and the modulatory effects of insulin are examined. In paper I, we used the patch-clamp technique to record synaptic and extrasynaptic GABA-A receptor-activated tonic currents from the granule cells of the dentate gyrus (DG) and CA3 pyramidal neurons along the dorsoventral axis of the mouse hippocampus. The results suggested cell type-specific variations in the inhibitory tone along the longitudinal hippocampal axis. In paper II, we analyzed both cell types in the mouse hippocampus and aimed to determine the effects of insulin on GABA signalling along the dorsoventral axis in the wild-type and Alzheimer’s disease animal model, tg-APPSwe mice. Physiological concentration of insulin modulated GABAergic synaptic and extrasynaptic tonic currents based on neuronal subtype and position along the axis in young wild-type mice. Furthermore, insulin normalized GABA-activated currents in aged tg-APPSwe mice to levels similar to those recorded in wild-type mice. In addition to the brain, GABA is present in blood and acts as a signalling molecule in immune cells. We show in paper III that GABA modulated cytokine release and the proliferation of activated CD4+ T cells isolated from normal individuals. These effects were differentially regulated by extracellular glucose concentration; the effects decreased as extracellular glucose concentration increased. GABA also modulated the expression of several genes and metabolism-related proteins in activated CD4+ T cells. Furthermore, insulin treatment increased the expression of the rho2 subunit of GABA-A receptors in activated CD4+ T cells and further enhanced the GABA effects. In paper IV, we observed that GABA inhibited the proliferation and altered cytokine release in a glucose concentration-dependent manner in activated CD4+ T cells isolated from type I diabetic patients. The findings of papers III and IV indicated a subset of samples called “non-responders”, wherein GABA did not affect the proliferation of activated CD4+ T cells but increased the release of a number of cytokines. The findings in my thesis increase the understanding of the modulatory effects of insulin on GABA signalling when GABA functions as a neurotransmitter and as an immunoregulatory molecule.