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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Alzheimer's disease (AD) is a progressive, neurodegenerative brain disorder characterized by extracellular accumulations of amyloid β (Aβ) peptides, intracellular accumulation of abnormal proteins, and early loss of basal forebrain neurons. Recent studies have indicated that the conformation of Aβ is crucial for neuronal toxicity, with intermediate misfolded forms such as oligomers being more toxic than the final fibrillar forms. Our previous work shows that Aβ blocks the potassium (K+) currents IM and IA in septal neurons, increasing firing rates, diminishing rhythmicity and firing coherence. Evidence also suggests that oxidative stress (OS) plays a role in AD pathogenesis. Thus we wished to determine the effect of oligomeric and fibrillar forms of Aβ1–42 on septohippocampal damage, oxidative damage, and dysfunction in AD. Oligomeric and fibrillar forms of Aβ1–42 were injected into the CA1 region of the hippocampus in live rats. The rats were sacrificed 24 hours and 1 month after Aβ or sham injection to additionally evaluate the temporal effects. The expression levels of the K+ voltage-gated channel, KQT-like subfamily, member 2 (KCNQ2) and the OS-related genes superoxide dismutase 1, 8-oxoguanine DNA glycosylase, and monamine oxidase A, were analyzed in the hippocampus, medial, and lateral septum. Our results show that both forms of Aβ exhibit time-dependent differential modulation of OS and K+ channel genes in the analyzed regions. Importantly, we demonstrate that Aβ injected into the hippocampus triggered changes in gene expression in anatomical regions distant from the injection site. Thus the Aβ effect was transmitted to anatomically separate sites, because of the functional coupling of the brain structures.

The medial septum/diagonal band complex (MSDB) controls hippocampal excitability, rhythms and plastic processes. Medial septal neuronal populations display heterogeneous firing patterns. In addition, some of these populations degenerate during age-related disorders (e.g. cholinergic neurons). Thus, it is particularly important to examine the intrinsic properties of theses neurons in order to create new agents that effectively modulate hippocampal excitability and enhance memory processes. Here, we have examined the properties of voltage-gated, K+ currents in electrophysiologically-identified neurons. These neurons were taken from young rat brain slices containing the MS/DB complex. Whole-cell, patch recordings of outward currents were obtained from slow firing, fast-spiking, regular-firing and burst-firing neurons. Slow firing neurons showed depolarization-activated K+ current peaks and densities larger than in other neuronal subtypes. Slow firing total current exhibited an inactivating A-type current component that activates at subthreshold depolarization and was reliably blocked by high concentrations of 4-AP. In addition, slow firing neurons expressed a low-threshold delayed rectifier K+ current component with slow inactivation and intermediate sensitivity to tetraethylamonium. Fast-spiking neurons exhibited the smaller IK and IA current densities. Burst and regular firing neurons displayed an intermediate firing phenotype with IK and IA current densities that were larger than the ones observed in fast-spiking neurons but smaller than the ones observed in slow-firing neurons. In addition, the prevalence of each current differed among electrophysiological groups with slow firing and regular firing neurons expressing mostly IA and fast spiking and bursting neurons exhibiting mostly delayer rectifier K+ currents with only minimal contributions of the IA. The pharmacological or genetic modulations of these currents constitute an important target for the treatment of age-related disorders.

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