The dominant inhibitory neurotransmitter of the mammalian brain is gamma- aminobutyric acid (GABA). Understandably, GABAergic inhibition is critically involved in both short- and long-term regulation of neuronal excitability in virtually all modes of functioning and malfunctioning of the mammalian brain. The proposed experiments will address fundamental issues related to the pre- and postsynaptic regulation of GABA-mediated inhibition. These include: 1) some of the cellular factors and second messengers responsible for the regulation of postsynaptic responses to endogenously released GABA, 2) the presence of endogenous ligands for benzodiazepine receptors, 3) the role of GABA uptake in modulation of intrinsic inhibition, 4) the mechanism of action of some anesthetics and anticonvulsants, 5) the conditions during which postsynaptic GABAB receptors are activated by spontaneously released GABA, and 6) some of the regulatory mechanisms governing the release of GABA from inhibitory synaptic terminals. The GABAergic inhibition will be studied using whole-cell patch clamp recordings in adult rat brain slices maintained in vitro at physiological temperatures. Such recordings permit the resolution of very small amplitude spontaneous inhibitory postsynaptic currents (sIPSCs) some of which result from the simultaneous activation of less than 15 GABA receptor/channels. The sIPSCs stem from the endogenous release of GABA packets and accurately reflect the tonic inhibition intrinsic to the mammalian brain. Thus, using the neurons themselves as biosensors, the measurement of sIPSC kinetics and frequencies is the highest resolution and most accurate method presently available to assess the modulation of GABAergic inhibition in the brain. The study will determine the features of the GABAergic system's built-in divergence. Since at least two fundamentally different classes of GABA receptors (GABAA and GABAB) co- exist in nerve cells, the differential activation of the two receptor systems by spontaneously released and ambient levels of GABA will be established. The proposed study will furnish a better understanding of the modulation of inhibition in the mammalian brain, and will have substantial implications on several normal physiological processes (e.g., learning and memory) and pathological states of brain function (e.g., epilepsy, Alzheimer's, Huntington's or Parkinson's disease, and psychiatric disorders). Furthermore, by addressing several basic issues related to the mechanism underlying spontaneous release of neurotransmitter substances in general, the study will ultimately contribute to unveiling some of the common modes of cell-to-cell communication in the mammalian brain.
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