| Popis: |
γ-aminobutyric acid type A receptors (GABAA receptors) underlie the majority of inhibitory synaptic transmission in the brain. Modulation of GABAergic activity occurs in development and normal physiological functioning of the brain, and changes to GABAergic function has been implicated in numerous neurological disorders including epilepsy. Neurosteroids, metabolites of steroid hormones, and kinases are known to modulate GABAA receptor mediated currents in health and disease. This thesis aims to investigate the effects of kinases and neurosteroids on modulating GABAA receptor-mediated currents in cortical pyramidal cells and their effects on the piriform cortex (PCtx) circuit in naïve rats and in rats after kindling (animal model of epilepsy). Specifically, we investigated: 1) The effects of kinase activators on neurosteroid-induced modulation of GABAA receptor mediated currents, using inhibitory neurosteroid tetrahydrodeoxy-corticosterone (THDOC) and excitatory neurosteroid pregnenolone sulfate (PregS). 2) The effect of neurosteroid THDOC and protein kinase modulation on the PCtx circuit 3) The effect of THDOC and kinase modulation in the PCtx after kindling We found that kinases differentially modulate the potentiating effect of THDOC on phasic and tonic inhibition, where they suppressed enhancement of tonic inhibition, but had no effect on phasic inhibitory postsynaptic currents (IPSCs). By contrast, kinases did not modulate the effect of excitatory neurosteroid PregS on phasic and tonic inhibition. In the PCtx circuit, THDOC suppressed the activity of the circuit, and this effect was blocked by prior kinase activation. After kindling, we found that THDOC no longer suppressed the circuit activity. Protein kinase C activation partially restored the effect of THDOC after kindling. Our findings show that protein kinase activities regulate neurosteroid-mediated modulation of GABAergic inhibition and that regulation of protein kinase activity may be able to restore normal neurosteroid functioning in epilepsy. |
