Effect of GABAA Receptor Clustering on Phasic and Tonic Inhibition in the Hippocampus

Inhibitory transmission plays a major role in information processing in the brain since it integrates excitatory signals and defines the gain between neural input and output. γ-Amino butyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain. By activating GABAA and GABAB receptors this neurotransmitter inhibits neuronal firing and stabilizes the membrane potential near the resting value. In particular GABAA receptors are permeable to chloride ions and are responsible for phasic and tonic hyperpolarizing responses. GABA-mediated currents are the result of rapid, sequential events including transmitter release from the presynaptic terminal, transmitter diffusion within and outside the cleft and post-synaptic receptors gating. The kinetics of each of these processes is crucial in determining the shape of post-synaptic currents. Therefore the modulation of any of these events leads to the heterogeneity of GABAergic responses and to changes in the potency of inhibition. In this thesis I have studied the sources of such variability at presynaptic/cleft and postsynaptic level. At presynaptic/cleft level I have focused on the influence of the agonist concentration profile in the synaptic cleft on GABA-mediated synaptic currents. Fast-off competitive antagonists and computer simulations allowed estimating the range of variability of the peak concentration and the speed of GABA clearance form the synaptic cleft. At postsynaptic level particular attention has been attributed to the impact of GABAA receptors clustering on both phasic and tonic GABAA-mediated inhibition. With ultrafast applications of GABA and computer simulations it was possible to describe the modulation of GABAA receptor gating induced by clustering.