Medial septal benzodiazepine receptors modulate hippocampal evoked responses and long-term potentiation

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Infusion of benzodiazepine (BDZ) receptor ligands into the medial septum (NIS) produces a bidirectional modulation of spatial memory retention. The present experiments sought to determine the effects of BDZ ligands upon synaptic responses and long-term potentiation (LTP) in the dentate gyrus following electrical stimulation of the angular bundle. Intraseptal infusion of the BDZ agonist, chlordiazepoxide, decreased the amplitude of the evoked population spike and increased paired-pulse facilitation at a 150-ms interstimulus interval (ISI) in a dose-dependent manner. Intraseptal infusion of the BDZ antagonist, flumazenil (10 nmol), enhanced the amplitude of the dentate population spike and also increased paired-pulse facilitation at the 150-ms ISI. There was no effect of either BDZ receptor ligand upon the slope of the rising phase of the evoked population excitatory postsynaptic potential (pEPSP). Intraseptal flumazenil also significantly enhanced the magnitude of dentate LTP induced by high-frequency stimulation of the angular bundle. Intraseptal chlordiazepoxide failed to alter LTP induction. These results indicate that intraseptal infusion of an amnestic dose of the BDZ ligand, chlordiazepoxide, decreases the excitatory responsiveness of the dentate gyros to its synaptic input from entorhinal cortex. In contrast, the promnestic BDZ ligand, flumazenil, enhances dentate granule cell responsivity, and facilitates synaptic plasticity in the dentate gyrus network. Taken together these data suggest that the memory impairing and memory enhancing action of these compounds may be a function of their ability to alter hippocampal physiology during a critical phase of memory. The potential role of septodentate cholinergic and GABAergic projections in the present observations is discussed.