NORADRENERGIC REGULATION OF SYNAPTIC INHIBITION

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Synaptic physiology in the hippocampus is characterized by strong local inhibitory circuits that the influence of excitatory synaptic transmission. The neurotransmitter norepinephrine (NE), regulates synaptic inhibition in the hippocampus in two important ways. Acting at alpha adrenoceptors, NE produces disinhibition, a reduction in stimulus- evoked inhibitory postsynaptic potentials, through an unknown action on inhibitory interneurons. It also increases tonic synaptic inhibition by directly stimulating action potential discharge in interneurons. Both of these actions may participate in the well-known, but poorly understood, action of NE to reduce epileptic activity eg 54,55. Here we propose a thorough examination of the disinhibitory action of NE, to define its underlying physiological mechanisms. The proposed studies will concentrate on the actions of NE on hippocampal interneurons; Previously, we have identified three mechanisms that may underlie adrenergic disinhibition; Blockade of excitatory synaptic activation of oriens/alveus interneurons, direct depolarization of these interneurons, leading to loss of responsiveness, and, hyperpolarization of lacunosum- molecular interneurons, leading to a loss of distal slow inhibition in area CA1 of the hippocampus. Experiments will be directed at determining a mechanism for these effects and understanding their role in controlling hippocampal excitability.