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.

A series of experiments was carried out testing the hypothesis that the septal region decreases the hippocampal susceptibility to hyperexcitability states through theta rhythm generation. Medial septal neurons were simultaneously recorded with hippocampal field potentials to investigate the septo-hippocampal function in the pilocarpine model of chronic epilepsy. The theta rhythm from chronically epileptic rats had lower amplitude (20% less) and higher frequency than controls (from 3.38 to 4.25 Hz), suggesting that both generator and pacemaker structures are affected during the epileptic process. At the cellular level, the group of rhythmically bursting firing medial septal neurons, in the epileptic animals, significantly and chronically increased their firing rates in relation to controls (from 13.86 to 29.14 spikes/s). Peristimulus histograms performed around hippocampal sharp waves showed that all high-frequency firing neurons, including rhythmically bursting neurons and most slow firing neurons, decreased firing rates immediately after hippocampal epileptic discharges. Thus inhibitory hippocampo-septal influences prevail during hippocampal epileptic discharges. The occurrence of epileptic discharges was reduced 86-97% of the number observed during spontaneous theta and theta induced by sensory (tail pinch) or chemical stimulation (carbachol), suggesting that the presence of the theta state regardless of how it was produced was responsible for the reduction in epileptic discharge frequency. The understanding of the theta rhythm "anti-epileptic" effect at the cellular and molecular levels may result in novel therapeutic approaches dedicated to protect the brain against abnormal excitability states.

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Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of hippocampal and cortical circuits and is crucial to the initiation and occurrence of oscillatory activities such as the hippocampal theta rhythm. Previous studies suggest that amyloid β peptide (Aβ) accumulation may trigger degeneration in AD. This study evaluates the effects of single injections of Aβ 1-40 into the medial septum. Immunohistochemistry revealed a decrease in septal cholinergic (57%) and glutamatergic (53%) neurons in Aβ 1-40 treated tissue. Additionally, glutamatergic terminals were significantly less in Aβ treated tissue. In contrast, septal GABAergic neurons were spared. Unitary recordings from septal neurons and hippocampal field potentials revealed an approximately 50% increase in firing rates of slow firing septal neurons during theta rhythm and large irregular amplitude (LIA) hippocampal activities and a significantly reduced hippocampal theta rhythm power (49%) in Aβ 1-40 treated tissue. Aβ also markedly reduced the proportion of slow firing septal neurons correlated to the hippocampal theta rhythm by 96%. These results confirm that Aβ alters the anatomy and physiology of the medial septum contributing to septohippocampal dysfunction. The Aβ induced injury of septal cholinergic and glutamatergic networks may contribute to an altered hippocampal theta rhythm which may underlie the memory loss typically observed in AD patients.

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