PHYSIOLOGY OF THE HIPPOCAMPAL INTERNEURON NETWORK

The overall objective of the proposal is to understand the role of GABAergic interneurons in normal and abnormal signaling processes in the cortex. Our recent studies show that there are networks of GABAergic interneurons within the hippocampus and neocortex in which the neurons are linked by excitatory connections. We have found that two different processes are involved in this recurrent excitation among GABAergic interneurons. In the first, GABA, which has generally been considered an inhibitory transmitter, acts instead as an excitatory transmitter between interneurons, causing a depolarization in the postsynaptic interneuron. In the second, the excitatory interconnections are maintained without chemical synaptic transmission, possibly through electronic junctions. The proposed studies will 1) investigate why GABA is having a depolarizing effect, and specifically, the ionic basis of the GABA-mediated depolarizing current; 2) identify which CA1 interneurons are interconnected by the excitatory GABAergic synapses and the distribution and pharmacological properties of the hyperpolarizing and depolarizing GABAergic synapses onto these cells; and 3) identify the CA1 interneurons which communicate by non-chemical means and examine the possible role of electrotonic junctions in their interconnections. Experiments will be carried out using microelectrodes and whole-cell voltage-clamp recording in hippocampal slices and whole-cell voltage clamp from acutely-dissociated hippocampal neurons taken from mature guinea pigs. In addition, the morphology of electrophysiologically- characterized interneurons in the slice will be identified by introducing the marker neurobiotin into the cells through the intracellular recording electrode. Deficiencies of GABAergic inhibition in the cortex can result in epileptogenesis. The proposed studies will provide valuable information on two previously unknown powerful excitatory processes which interconnect GABAergic interneurons. These processes are considered powerful because they can produce rhythmic synchronized discharge of GABAergic interneurons independent of the glutamate-driven excitatory synaptic events. The proposed studies will contribute to the understanding of the role of GABAergic interneurons in the normal and abnormal signaling processes in the mammalian cortex.