Neuroscience
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Expression Profiles of Metallothionein I/II and Megalin in Cuprizone Model of De- and Remyelination.
Copper chelator cuprizone (CPZ) is neurotoxicant, which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. To explore the participation of metallothioneins (MTs) in these processes, in this study we analyzed the expression profiles of MT-I/II and their receptor megalin (low-density lipoprotein receptor related protein-2) in the brain of mice subjected to different protocols of CPZ feeding. ⋯ Moreover, in numerous cortical neurons and progenitor cells the signs of MT/megalin interactions and Akt1 phosphorylation was found supporting the hypothesis that MTs secreted from the astrocytes might directly affect the neuronal differentiation and survival. Furthermore, in mice treated with CPZ for 5 weeks the prominent MTs and megalin immunoreactivities were found on several neural stem cells and oligodendrocyte progenitors in subgranular zone of dentate gyrus and subventricular zone of lateral ventricles pointing to high modulatory effect of MTs on adult neuro- and oligodendrogenesis. The data show that MT I/II perform important cytoprotective and growth-regulating functions in remyelinating processes activated after toxic demyelinating insults.
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Subarachnoid hemorrhage (SAH) is a well-known hemorrhagic stroke with high rates of morbidity and mortality where patients frequently experience cognitive dysfunction. This study explores a potential treatment for cognitive dysfunction following SAH with the demonstration that multi-target drug cattle encephalon glycoside and ignotin (CEGI) can relieve cognitive dysfunction by decreasing hippocampal neuron apoptosis following SAH in rats. Experimentally, 110 male SD rats were separated at random into Sham (20), SAH + Vehicle (30), SAH + 4 ml/kg CEGI (30), and SAH + 1 ml/kg CEGI groups (30) and an endovascular perforation model was created to induce SAH. ⋯ This finding was associated with an observed decrease in Bax/Bcl-2 ratio, cytochrome-c and PUMA expression, and the suppression of caspase-3 activation following SAH. In Morris water maze tests, the SAH + 4 ml/kg CEGI group demonstrated a decreased escape latency time and increase in time spent in the target quadrant as well as crossing times of platform region. These results indicate that high doses of CEGI can decrease hippocampal neuron apoptosis and relieve cognitive dysfunction in rats, suggesting that multitarget-drug CEGI exhibits a neuroprotective effect in SAH via the mitochondrial apoptosis pathway.
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Short-term plasticity enables synaptic strength to be dynamically regulated by input timing. Excitatory synapses arising from the same axon can have profoundly different presynaptic forms of short-term plasticity onto inhibitory and excitatory neurons. We previously showed that Schaffer collateral synapses onto most hippocampal CA1 stratum radiatum interneurons have less paired-pulse facilitation than synapses onto CA1 pyramidal cells, but little difference in steady-state short-term depression. ⋯ These target-cell specific differences in short-term plasticity reduce the strength of excitatory input onto interneurons relative to pyramidal cells, and of depression interneurons relative to facilitation interneurons, during high frequency portions of the train. This occurs to a similar extent at 25 °C and at 33 °C, and is even greater at physiological extracellular calcium. Target-cell specific differences in short-term plasticity enable synapses to have different temporal filtering characteristics, which may help to dynamically regulate the balance of inhibition and excitation in CA1.
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Changes in inhibition following traumatic brain injury (TBI) appear to be one of the major factors that contribute to excitation:inhibition imbalance. Neuron pathology, interneurons in particular evolves from minutes to weeks post injury and follows a complex time course. Previously, we showed that in the long-term in diffuse TBI (dTBI), there was select reduction of specific dendrite-targeting neurons in sensory cortex and hippocampus while in motor cortex there was up-regulation of specific dendrite-targeting neurons. ⋯ However, DG of hippocampus now showed reduction of dendrite-targeting inhibitory neurons. Finally, with respect to motor cortex, there was an upregulation of dendrite-targeting interneurons in the supragranular layers at 24 h returning to normal levels by 2 weeks. Overall, our findings reconfirm that dendritic inhibition is particularly susceptible to brain trauma, but also show that there are complex brain-area-specific changes in inhibitory neuronal numbers and in compensatory changes, rather than a simple monotonic progression of changes post-dTBI.