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The two neuronal populations that have been typically investigated in the septum use acetylcholine and GABA as neurotransmitters. The existence of noncholinergic, non-GABAergic, most likely glutamatergic septal neurons has recently been reported. However, their morphological characteristics, numbers, distribution, and connectivity have not been determined. Furthermore, the projection of septal glutamatergic neurons to the hippocampus has not been characterized. To address these issues, subpopulations of cholinergic and GABAergic neurons were identified by immunohistochemistry. In addition, the retrograde tracer fluorogold was injected into the hippocampus to determine the characteristics of a glutamatergic septo-hippocampal projection. Our work revealed that although glutamatergic neurons are found throughout the septum, they concentrate in medial septal regions. Using stereological probes, approximately 16,000 glutamatergic neurons were estimated in the medial septal region. Triple immunostaining showed that most glutamatergic neurons do not immunoreact with cholinergic or GABAergic neuronal markers (anti-ChAT or anti-GAD67 antibodies, respectively). Fluorogold injections into CA1, CA3, and dentate gyrus of the hippocampus showed that septal glutamatergic neurons project to each of these hippocampal regions, forming approximately 23% of the septo-hippocampal projection. Most cell bodies of septo-hippocampal glutamatergic neurons were located in the medial septum. The remaining cell bodies were found in the diagonal band. This data shows that glutamatergic neurons constitute a significant neuronal population in the septum and that a subpopulation of these neurons projects to hippocampal regions. Thus, the septo-hippocampal projection needs to be reconsidered as a three neurotransmitter pathway.

Basal forebrain cholinergic neurons are severely depleted early in Alzheimer's disease and appear particularly susceptible to amyloid /3-peptide (A/3) toxicity in vivo. To model this effect in vitro, a cholinergic septal cell line (SN56) was exposed to Af3. SN56 cells exhibited a tetraethylammonium (TEA)-sensitive outward Kcurrent with delayed rectifier characteristics. Increases of 64% (±19; p < 0.02) and 44% (±12; p < 0.02) in Kc urrent density were noted 6-12 and 12-18 h following the addition of A~3to SN56 cell cultures, respectively. Morphological observation and staining for cell viability showed that 25 ± 4 and 39 ± 4% of SN56 cells were dead after 48-and 96-h exposures to A~,respectively. Perfusion of SN56 cells with 10-20 mMTEA blocked 71 ± 6 to 92 ± 2% of the outward currents, widened action potentials, elevated [Ca 2~],,and inhibited 89 ± 14 and 68 ±

Information processing and storing by brain networks requires a highly coordinated operation of multiple neuronal groups. The function of septal neurons is to modulate the activity of archicortical (e.g. hippocampal) and neocortical circuits. This modulation is necessary for the development and normal occurrence of rhythmical cortical activities that control the processing of sensory information and memory functions.Damage or degeneration of septal neurons results in abnormal information processing in cortical circuits and consequent brain dysfunction. Septal neurons not only provide the optimal levels of excitatory background to cortical structures, but they may also inhibit the occurrence of abnormal excitability states.

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