The hippocampus is a brain region known to be necessary for normal learning and memory in laboratory animals and in humans. Inhibitory interneurons exert powerful control over the electrical output of the hippocampus. The interneurons feed forward and feed back to inhibit both the cell body and dendrites of the excitatory pyramidal cells. Each interneuron synapses onto over one hundred pyramidal cells, and excitation or inhibition of small numbers of interneurons can therefore control excitability in large areas of the hippocampus. The interneurons may thus act as a gate, permitting shifts from one output pattern to another. Modulation of subgroups of interneurons (e. g., those responsible for inhibition of dendritic regions) could cause not only gross inhibition or disinhibition, but a variety of fine-tuned alterations in hippocampal output. The hippocampus is innervated by afferents from subcortical and midbrain nuclei that trigger various behavioral states in vivo. The primary function of this innervation in the hippocampus may be modulation of interneurons. A particularly well-studied example of a change in overall hippocampal excitability is the shift from desynchronized activity to theta rhythm observed in hippocampal EEG recordings. The theta rhythm is turned on by cholinergic afferents from the septum and serotonergic afferents from the raphe nucleus, which have been shown to make synaptic contacts on hippocampal interneurons. The proposed experiments will study the modulation of interneurons by acetylcholine and serotonin, as a test case of the idea that a shift from one state of hippocampal activity to another can be accomplished by modulation of interneurons. This work will define the physiological and pharmacological differences between populations of hippocampal interneurons, and will suggest ways in which distinct interneuron groups may interact to control hippocampal output. An understanding of the effects of acetylcholine and serotonin on this largely unstudied subgroup of neurons is essential for understanding changes that may occur in the hippocampus under a variety of pathological conditions, including epileptiform activity, Alzheimers disease, and drug therapies used in psychiatric treatments that antagonize cholinergic or serotonergic function. Experiments will utilize whole cell recordings of interneurons in two regions of the rat hippocampal slice. Interneurons both in stratum oriens and in stratum lacunosum/moleculare will be recorded from during application of acetylcholine and serotonin. Stimulation of regions of the slice likely to contain axons originating from septum or raphe will be used to study effects of endogenously released transmitter. The ionic basis and the receptor subtypes responsible for any observed effects will be defined using pharmacological tools. After recording, cells will be labelled with biocytin and reacted with avidin-HRP and anti-glutamate decarboxylase antibody to confirm their morphology, and GABAergic identity.
