P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. To understand the relationship between tau pathology and behavioral impairments, we comprehensively assessed behavioral abnormalities in a mouse tauopathy model expressing the human P301S mutant tau protein in the early stage of disease to detect its initial neurological manifestations. Behavioral abnormalities, shown by open field test, elevated plus-maze test, hot plate test, Y-maze test, Barnes maze test, Morris water maze test, and/or contextual fear conditioning test, recapitulated the neurological deficits of human tauopathies with dementia. Furthermore, we discovered that prepulse inhibition (PPI), a marker of sensorimotor gating, was enhanced in these animals concomitantly with initial neuropathological changes in associated brain regions. This finding provides evidence that our tauopathy mouse model displays neurofunctional abnormalities in prodromal stages of disease, since enhancement of PPI is characteristic of amnestic mild cognitive impairment, a transitional stage between normal aging and dementia such as Alzheimer's disease (AD), in contrast with attenuated PPI in AD patients. Therefore, assessment of sensorimotor gating could be used to detect the earliest manifestations of tauopathies exemplified by prodromal AD, in which abnormal tau protein may play critical roles in the onset of neuronal dysfunctions

Down to atomic-scale intracellular water dynamics

Water constitutes the intracellular matrix in which biological molecules interact. Understanding its dynamic state is a main scientific challenge, which continues to provoke controversy after more than 50 years of study. We measured water dynamics in vivo in the cytoplasm of Escherichia coli by using neutron scattering and isotope labelling. Experimental timescales covered motions from pure water to interfacial water, on an atomic length scale. In contrast to the widespread opinion that water is ‘tamed' by macromolecular confinement, the measurements established that water diffusion within the bacteria is similar to that of pure water at physiological temperature

Altered Dopamine Modulation of Inhibition in the Prefrontal Cortex of Cocaine-Sensitized Rats

A functionally hypoactive prefrontal cortex (PFC) is thought to contribute to decreased cognitive inhibitory control over drug-seeking behavior in cocaine addicts. Alterations in PFC dopamine (DA) and γ-aminobutyric acid (GABA) transmission are involved in the development of behavioral sensitization to cocaine, and repeated exposure to cocaine decreases DA D2 receptor (D2R) function in the PFC. We used recordings in PFC slices from adult rats to investigate how repeated cocaine treatment followed by 2 weeks of withdrawal affects DA modulation of GABA transmission and interneuron firing. In agreement with previous results in drug-naïve animals we found that in saline-treated control animals DA (20 μM) modulated evoked inhibitory post-synaptic currents (eIPSCs) in a biphasic, time- and receptor-dependent manner. Activation of D2Rs transiently reduced, whereas D1 receptor activation persistently increased the amplitude of eIPSCs. In cocaine-sensitized animals the D2R-dependent modulation of eIPSCs was abolished and the time course of DA effects was altered. In both saline- and cocaine-treated animals the effects of DA on eIPSCs were paralleled by distinct changes in spontaneous IPSCs (sIPSCs). In cocaine-treated animals the alterations in DA modulation of eIPSCs and sIPSCs correlated with a lack of D2R-specific reduction in action potential-independent GABA release, which might normally oppose D1-dependent increases in GABA transmission. Recordings from interneurons furthermore show that D2R activation can increase current-evoked spike firing in saline, but not in cocaine-treated animals. Altered DA regulation of inhibition during cocaine withdrawal could disturb normal cortical processing and contribute to a hypoactive PFC