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Plasticity of GABAergic Inhibition


&gamma-aminobtutyric acid (GABA) is a transmitter molecule found in several organs and virtually all organisms. In the vertebrate central nervous system it is the major inhibitory neurotransmitter. Here GABA released by GABAergic neurons binds to GABA receptors and regulates neuronal excitability, network synchrony and neuronal development. GABAA receptors (GABAARs) are highly conserved ligand-gated ion channels permeable to Cl- and HCO3-, and upon binding GABA they generate currents that can be functionally distinguished in phasic or tonic. Physiology of tonic GABAergic conductances is of particular interest as these exercise powerful constrain on neuronal excitability and gain. Tonic inhibition is mediated by GABAARs containing &delta or &alpha5 subunits localized outside of the synaptic cleft and activated by ambient GABA. Object of this dissertation is plasticity of &delta- GABAARs, as their function and distinct pharmacology makes them relevant to many human diseases. &delta-GABAARs are naturally insensitive to benzodiazepines while uniquely sensitive to low concentrations of neurosteroids, which act on them as positive allosteric modulators. These endogenous steroids are the neuroactive form of progesterone, cortisol and testosterone. They are locally synthetized in both neurons and glia and their brain concentration varies in parallel with oscillations in plasma precursors. The present work shows how during times of altered neurosteroid production &delta-GABAARs expression homeostatically changes with functional consequences on neuronal network functioning. In particular, plasticity of &delta-GABAARs during pregnancy and the postpartum affects hippocampal excitability and &gamma oscillations frequency in vitro. Moreover, over the ovarian cycle, plasticity of &delta-GABAARs on interneurons is necessary for fluctuations in &gamma oscillations amplitude in vivo. More and more evidence suggests an involvement of &delta-GABAARs in different kinds of neurological and psychiatric disorders, such as epilepsies, postpartum depression, pre-menstrual dysphoric disorder, and schizophrenia. Interestingly a convenient therapeutic strategy may be available, given the anatomical distribution of these receptors. In fact, &delta-GABAARs expressed on excitatory neurons of the cortex contain &alpha4 subunits, whereas on interneurons they contain &alpha1 subunits. This allows to pharmacologically differentiate &delta-GABAARs on specific neuron. Development of drugs optimized to selectively modify &delta-GABAA-mediated tonic inhibition of excitatory or inhibitory neurons may lead to critical clinical applications.

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