Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer's disease model.

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer's disease, are intracellular silver and thioflavin S-staining aggregates that emerge from earlier accumulation of phospho-tau in the soma. Whether soluble misfolded but nonfibrillar tau disrupts neuronal function is unclear. Here we investigate if soluble pathological tau, specifically directed to the entorhinal cortex (EC), can cause behavioral or synaptic deficits. We studied rTgTauEC transgenic mice, in which P301L mutant human tau overexpressed primarily in the EC leads to the development of tau pathology, but only rare NFT at 16 months of age. We show that the early tau lesions are associated with nearly normal performance in contextual fear conditioning, a hippocampal-related behavior task, but more robust changes in neuronal system activation as marked by Arc induction and clear electrophysiological defects in perforant pathway synaptic plasticity. Electrophysiological changes were likely due to a presynaptic deficit and changes in probability of neurotransmitter release. The data presented here support the hypothesis that misfolded and hyperphosphorylated tau can impair neuronal function within the entorhinal-hippocampal network, even prior to frank NFT formation and overt neurodegeneration.

Effects of methylphenidate and morphine on delay-discount functions obtained within sessions.

Four rats responded under a "self-control" procedure designed to obtain delay-discount functions within sessions. Each session consisted of seven blocks, with seven trials within each block. Each block consisted of two initial forced-choice trials followed by five free-choice trials. On choice trials, the rats could press either of two retractable levers. A press on one lever was followed by presentation of a smaller reinforcer (a single dipper presentation of a sucrose solution); a press on the other lever was followed by presentation of a larger reinforcer (four consecutive dipper presentations). The delay associated with the smaller reinforcer always was 0 s, whereas the signaled delay associated with the larger reinforcer increased across blocks (from 0 to 50 s). Under these conditions, the percentage of choices of the larger reinforcer decreased across blocks, and relatively reliable delay-discount functions were obtained within sessions. Doses of methylphenidate (1.0 to 17.0 mg/kg) and morphine (0.3 to 17.0 mg/kg) were then administered prior to selected sessions. Typically, intermediate doses of methylphenidate shifted the discount functions to the right (increased choices of the larger reinforcer). For 2 of the rats, this effect was pronounced; for the other 2 rats, this effect occurred after the range of delays for the larger reinforcer was decreased (0 to 20 s). On the other hand, in most cases morphine produced a slight leftward shift in the discount function (decreased choices of the larger reinforcer). The present procedure appears to be a useful and efficient method to characterize drug effects on an entire delay-discount function. As with many procedures used to study self-control choices, however, sources of control other than reinforcement delay and amount may have been operating in the present study, and these sources must be considered when interpreting drug effects.