Neuroscience
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Synapse or dendritic spine loss is the strongest correlate of cognitive decline in Alzheimer's disease (AD), and neurofibrillary tangles (NFTs), but not amyloid-β plaques, associate more closely with transition to mild cognitive impairment. Yet, how dendritic spine architecture is affected by hyperphosphorylated tau is still an ongoing question. To address this, we combined cell and biochemical analyses of the Tau P301S mouse line (PS19). ⋯ This suggests that CA1 pyramidal neurons in PS19 mice may undergo spine remodeling in response to tau accumulation and age. In the mPFC, spine density was similar among PS19 mice and NTG littermates at 6 and 9 months, but age-related reductions in synaptic tau levels were observed among PS19 mice. Collectively, these studies reveal brain region-specific changes in dendritic spine density and morphology in response to age and the presence of hyperphosphorylated tau in the PS19 mouse line.
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Substance P (SP) regulates inhibitory synaptic transmission mediated by GABAA receptors in the cerebral cortex; however, SP-mediated regulation of excitatory synaptic transmission remains poorly understood. We performed whole-cell patch-clamp recordings from pyramidal neurons to examine the effects of SP on excitatory postsynaptic currents (EPSCs) mediated via AMPA receptors in the insular cortex (IC), which is involved in nociceptive information processing. First, EPSCs evoked by minimal electrical stimulation (eEPSCs) including stepwise EPSCs and failure events, were examined. ⋯ NO imaging using the fluorescent probe DAX-J2 Red supports this hypothesis: SP increased the fluorescence intensity of DAX-J2 Red in some GABAergic neurons. Furthermore, both L-NAME, an NOS inhibitor, and PTIO, an NO scavenger, diminished the SP-induced suppression of eEPSCs. These results suggest that the activation of presynaptic NK1 receptors contributes to SP-induced eEPSC suppression by activating the NO synthesis pathway in GABAergic neurons. (246 words).
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The rat auditory cortex is divided anatomically into several areas, but little is known about the functional differences in information processing among these areas. Three tonotopically organized core fields, namely, the primary (A1), anterior (AAF), and ventral (VAF) auditory fields, as well as one non-tonotopically organized belt field, the dorsal belt (DB), were identified based on their response properties. Compared to neurons in A1, AAF and VAF, units in the DB exhibited little or no response to pure tones but strong responses to white noise. ⋯ Responses to repeated white noise were also examined. In contrast to neurons in A1, AAF and VAF, DB neurons could not follow repeated stimulation at a 300 ms inter-stimulus interval (ISI) and showed a significant steeper ISI tuning curve slope when the ISI was increased from 300 ms to 4.8 s. These results indicate that the DB processes auditory information on broader spectral and longer temporal scales than the core regions, reflecting a distinct role in the hierarchical cortical pathway.
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Demyelination is a well-known pathological process in CNS disorders such as multiple sclerosis (MS). It provokes progressive axonal degeneration and functional impairments and no efficient therapy is presently available to combat such insults. Recently, we have shown that etazolate, a pyrazolopyridine compound and an α-secretase activator, was able to promote myelin protection and remyelination after cuprizone (CPZ)-induced acute demyelination in C57Bl/6 mice. ⋯ Spatial memory evaluated was not affected either by CPZ intake or etazolate treatment in both protocols. Altogether, this study shows that the beneficial effect of etazolate upon demyelination does not occur at the gene expression level at the time points studied. Furthermore, our results also highlight the difficulty in revealing functional sequelae following CPZ intoxication.
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The postsynaptic density (PSD) is a complex subcellular domain important for postsynaptic signaling, function, and plasticity. The PSD is present at excitatory synapses and specialized to allow for precise neuron-to-neuron transmission of information. ⋯ Glutamatergic synaptic dysfunction affecting PSD morphology and signaling events have been described in many neurodegenerative disorders, either sporadic or familial forms. Thus, in this review we describe the main protein players forming the PSD and their activity, as well as relevant modifications in key components of the postsynaptic architecture occurring in Huntington's, Parkinson's and Alzheimer's diseases.