The broad, long-term objectives of this project are to provide physiological and pharmacological analyses of the synaptic organization of efferent, afferent, and intrinsic connections of the rat subicular complex and entorhinal cortex. First, physiological studies of efferent projections from these structures will be continued. Work will concentrate on projections from the subicular complex and entorhinal cortex to the prefrontal cortex. In order to achieve this objective, the subicular complex and entorhinal cortex will be stimulated electrically, and synaptic potentials in response to this stimulation will be recorded intracellularly in the prefrontal cortex. Target neurons in the prefrontal cortex will be injected intracellularly with horseradish peroxidase (HRP) in order to establish their dendritic and axonal morphology. Second, a pharmacological analysis of projections from the subicular complex to the entorhinal cortex will be conducted, using multibarrel iontophoretic techniques. The pharmacological studies will be designed to test the hypothesis that the excitatory responses in entorhinal principal and inhibitory cells are mediated by glutamatergic transmission; and that inhibitory responses are mediated by GABAergic transmission, secondary to glutamatergic excitation of local inhibitory neurons (feedforward inhibition). Specific antagonists of GABA A and GABA B receptors will be used in order to determine the receptor subtype(s) responsible for the inhibitory responses. Third, a pharmacological analysis of the projections from the subicular complex and entorhinal cortex to the amygdala and to the prefrontal cortex will be conducted. It is hypothesized that glutamatergic and GABAergic receptors mediate feedforward inhibition within these targets, and effort will be concentrated on establishing the roles of receptor subtypes. Fourth, the physiological action of projections to the subicular complex and entorhinal cortex from the prefrontal cortex will be determined. In particular, it is proposed 1) to establish whether inhibitory responses to prefrontal stimulation are mediated by inhibitory neurons located within the subicular complex and entorhinal cortex and 2) to establish the dendritic morphology and pattern of axonal projections of responsive target neurons by injecting them intracellularly with HRP. The proposed intracellular and pharmacological studies attack problems that can best be studied at the systems level in the intact, in vivo preparation. The subicular complex and entorhinal cortex participate in medically-refractory temporal lobe seizures, and appear to be early targets of cell death in Alzheimer's disease. Accordingly, a better understanding of these neuronal systems can provide insight into the pathophysiology associated with these diseases.
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