Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

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Numerous reports indicate that learning and memory of conditioned responses are accompanied by genesis of dendritic spines in the hippocampus, although there is a conspicuous lack of information regarding spine modifications after behavioral extinction. There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training.

Background: An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies.