CELLULAR PHARMACOLOGY AND PHYSIOLOGY OF SEPTAL NEURONS

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The dorsolateral septal nucleus (DLSN) is an integral link in the septohippocampal pathway (DLSN - Medial septum-Diagonal Band of Broca - hippocampus - DLSN). Although earlier anatomical studies had demonstrated its essential position in this pathway, the functional roles of neurons within the DLSN were unclear. We have utilized an in vitro brain slice preparation from rats to record intracellularly from the DLSN in order to provide fundamental information about the physiological, pharmacological, and anatomical properties of individual DLSN neurons. Our work and lesion studies with ibotenic acid support our original hypothesis that the DLSN may serve as site for the induction, maintenance, and expression of theta rhythm. This study will test four hypotheses which suggest cellular mechanisms to explain the induction of theta rhythm in the DLSN. Four specific aims will be addressed to test each of these hypotheses: 1) determine whether specific subtypes of cholinergic or GABAergic receptors can induce theta rhythm by regulation of voltage-dependent conductances on specific types of DLSN neurons; 2) determine if activation of cholinergic of GABAergic receptor subtypes can produce disinhibition in the DLSN and the induction of theta rhythm; 3) characterize the subtypes that modulate a non- specific cationic conductance which can induce theta rhythm; and 4) characterize the pharmacology of a metabotropic excitatory amino acid receptor which can induce LTP and possibly theta rhythm in the DLSN. We suggest that theta rhythm functions normally to facilitate (motivate) an individual to adapt (plasticity) and to facilitate and mediate such complex behaviors as learning and memory. If theta rhythm is not expressed or is expressed excessively, as under unusual emotional circumstances, e.g. stress; or in disease states, e.g., schizophrenia; or as a pathology of the aging process, e.g. dementia; or as a result of drug abuse; there may be an imbalance of three major transmitter systems, namely, GABAergic, cholinergic, and excitatory amino acid releasing. Each of these transmitter systems has been implicated in theta rhythm activity. As a result of this imbalance, aberrant behavior, rather than facilitation of normal behavior, occurs. This study will provide important basic information that may be applicable to clinical problems in mental health, since modification of theta rhythm and septal neuronal activity have been implicated in both normal and abnormal expressions of our emotions and in both normal and abnormal cognitive processes. Specific mental disorders that may benefit include: schizophrenia, anxiety, depression, dementia, Alzheimer's disease, and epilepsy.