Neuroscience
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Periventricular leukomalacia (PVL) is a severe type of white matter damage in premature infants and the most common cause of cerebral palsy. It is generally known to be caused by hypoxia and inflammation. Currently there is no effective treatment available, in part due to that the pathogenesis of the disease has not been well understood. ⋯ The electron microscopic images demonstrated that the microstructure of myelin structures was not significantly different between the wild-type and p38α MAPK CKO mice. In addition, oligodendrocyte degeneration in the corpus callosum white matter area was unaffected in the p38α MAPK CKO during and after the PVL induction. These data indicate that p38α MAPK in oligodendrocyte has minimal effect on myelination and oligodendrocyte survival in the mouse PVL model.
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Although the precise mechanism of action of antidepressant drugs remains elusive, the neuroplastic hypothesis has gained acceptance during the last two decades. Several studies have shown that treatment with antidepressants such as Fluoxetine is associated with enhanced plasticity in control animals, especially in regions such as the visual cortex, the hippocampus and the medial prefrontal cortex. More recently, the basolateral amygdala has been shown to be affected by Fluoxetine leading to a reopening of critical period-like plasticity in the fear and aggression circuits. ⋯ Here we show that Fluoxetine reorganizes inhibitory circuits through increased expression of the plasticity-related molecule PSA-NCAM which regulates interneuronal structure and connectivity. In addition, we demonstrate that treatment with this antidepressant alters the structure of somatostatin interneurons both at the level of dendritic spines and of axonal en passant boutons. Our findings suggest that new strategies targeting somatostatin interneuron activity might help us to better understand depression and the action of antidepressants.
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Strong evidence exists that Toll-like receptor (TLR)-mediated effects on microglia functional states can promote ictogenesis and epileptogenesis. So far, research has focused on the role of high-mobility group box protein 1 as an activator of TLRs. However, the development of targeting strategies might need to consider a role of additional receptor ligands. ⋯ The pronounced impact on the response to subsequent stimulations gives first evidence that genetic HSPA1A upregulation may also contribute to epileptogenesis. Thus, strategies inhibiting hsp70 or its expression might be of interest for prevention of seizures and epilepsy. However, conclusions about a putative pro-epileptogenic effect of hsp70 require further investigations in models with development of spontaneous recurrent seizures.
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β-Amyloid (Aβ) plays an important role in the early pathogenesis of Alzheimer's disease (AD). In vitro studies have demonstrated that Aβ oligomers induce hippocampal and neocortical neuronal death. However the neurotoxic mechanisms by which soluble Aβ oligomers cause neuronal damage and death remain to be fully elucidated. ⋯ The C-terminal region of NSP3 unbound to a Cas protein was necessary for the NSP3-induced acceleration of neuronal death, as was Cas-independent Rap1A activation downstream of NSP3. Moreover, NSP3 RNAi knockdown partially rescued Aβ-oligomer-treated neurons. These results indicate that NSP3 upregulation by soluble Aβ oligomers may accelerate neuronal death via Cas-independent Rap1A activation, implicating NSP3 in the pathogenesis of AD.
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Neonatal injury-induced exaggeration of pain hypersensitivity after adult trauma is a significant clinical challenge. However, the underlying mechanisms remain poorly understood. Growing evidence shows that spinal Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) contributes to chronic pain in adult rodents. ⋯ Finally, no alternation of SHP2 phosphorylation in the dorsal root ganglion and dorsal root of nIN-IN rats as well as PI3K expression in the dorsal root of nIN-IN rats intrathecally treated with NSC-87877 or SHP2 siRNA is observed. These results suggest that the phosphorylation and expression of SHP2 in the spinal dorsal horn play vital roles in neonatal incision-induced exaggeration of adult incisional pain via PI3K. Thus, SHP2 and PI3K may serve as potential therapeutic targets for exaggerated incisional pain induced by neonatal and adult injuries.