In Noonan Syndrome (NS) 30% to 50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated Ptpn11 mutations show hippocampal-dependent spatial learning impairments and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of the PTPN11D61G in adult hippocampus results in increased baseline excitatory synaptic function, deficits in LTP and spatial learning, which can all be reversed by a MEK inhibitor. Furthermore, brief treatment with lovastatin reduces Ras-Erk activation in the brain, and normalizes the LTP and learning deficits in adult Ptpn11D61G/+ mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.
Control of Ca flux between the cytosol and intracellular Ca stores is essential for maintaining normal cellular function. It has been well established in both neuronal and non-neuronal cells that stromal interaction molecule 1 (STIM1) initiates and regulates refilling Ca into the ER. Here, we describe a novel, additional role for STIM1, the regulation of free cytosolic Ca, and the consequent control of spike firing in neurons. Among central neurons, cerebellar Purkinje neurons express the highest level of STIM1, and they fire continuously in the absence of stimulation, making somatic Ca homeostasis of particular importance. By using Purkinje neuron-specific STIM1 knock-out (STIM1) male mice, we found that the deletion of STIM1 delayed clearance of cytosolic Ca in the soma during ongoing neuronal firing. Deletion of STIM1 also reduced the Purkinje neuronal excitability and impaired intrinsic plasticity without affecting long-term synaptic plasticity. In vestibulo-ocular reflex learning, STIM1 male mice showed severe deficits in memory consolidation, whereas they were normal in memory acquisition. Our results suggest that STIM1 is critically involved in the regulation of the neuronal excitability and the intrinsic plasticity of the Purkinje neurons as well as cerebellar memory consolidation. Stromal interaction molecule 1 (STIM1), which regulates the refilling of ER Ca, has been investigated in several systems including the CNS. In addition to a previous study showing that STIM1 regulates dendritic ER Ca refilling and mGluR1-mediated synaptic transmission, we provide compelling evidence describing a novel role of STIM1 in spike firing Purkinje neurons. We found that STIM1 regulates cytosolic Ca clearance of the soma during spike firing, and the interruption of this cytosolic Ca clearing disrupts neuronal excitability and cerebellar memory consolidation. Our results provide new insights into neuronal functions of STIM1 from single neuronal Ca dynamics to behavior level.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that leads to a progressive muscle wasting and paralysis. The pathological phenotypes are featured by severe motor neuron death and glial activation in the lumbar spinal cord. Proposed ALS pathogenic mechanisms include glutamate cytotoxicity, inflammatory pathway, oxidative stress, and protein aggregation. However, the exact mechanisms of ALS pathogenesis are not fully understood yet. Recently, a growing body of evidence provides a novel insight on the importance of glial cells in relation to the motor neuronal damage via the non-cell autonomous pathway. Accordingly, the aim of the current paper is to overview the role of astrocytes and microglia in the pathogenesis of ALS and to better understand the disease mechanism of ALS.
ABSTRACT. Previous animal studies have shown that transplantation of mesenchymal stem cells (MSCs) into spinal cord lesions enhances axonal regeneration and promotes functional recovery. We isolated the MSCs derived from fat, bone marrow, Wharton's jelly and umbilical cord blood (UCB) positive for MSC markers and negative for hematopoietic cell markers. Their effects on the regeneration of injured canine spinal cords were compared. Spinal cord injury was induced by balloon catheter compression. Dogs with injured spinal cords were treated with only matrigel or matrigel mixed with each type of MSCs. Olby and modified Tarlov scores, immunohistochemistry, ELISA and Western blot analysis were used to evaluate the therapeutic effects. The different MSC groups showed significant improvements in locomotion at 8 weeks after transplantation (P<0.05). This recovery was accompanied by increased numbers of surviving neuron and neurofilament-positive fibers in the lesion site. Compared to the control, the lesion sizes were smaller, and fewer microglia and reactive astrocytes were found in the spinal cord epicenter of all MSC groups. Although there were no significant differences in functional recovery among the MSCs groups, UCB-derived MSCs (UCSCs) induced more nerve regeneration and anti-inflammation activity (P<0.05). Transplanted MSCs survived for 8 weeks and reduced IL-6 and COX-2 levels, which may have promoted neuronal regeneration in the spinal cord. Our data suggest that transplantation of MSCs promotes functional recovery after SCI. Furthermore, application of UCSCs led to more nerve regeneration, neuroprotection and less inflammation compared to other MSCs.
Highlights d ASM activity is upregulated in brain and/or plasma of aged humans and mice d Brain endothelial cell is a main contributor of increased ASM in aging d Increased ASM in aging causes BBB impairment and neuronal dysfunction d It is regulated by caveolae-mediated transcytosis and ERM dephosphorylation
Canine mesenchymal stem cells (cMSCs) derived from umbilical cord blood represent a potentially useful source of stem cells for therapy. The aim of this study was to compare the effects of different transplantation times of cMSCs after spinal cord injury (SCI). A total of 21 dogs were subjected to SCI by balloon-induced compression of the first lumbar vertebrae for 12 h. Of the 21 dogs, 12 were divided into four groups of three according to the time of stem cell (1 × 10 6 ) transplantation at the injury site: control no treatment, 12 h, 1 week, and 2 weeks. The remaining 9 animals were negative harvest (HA) time controls for each treatment group (n = 3). Olby and Tarlov scores were used to evaluate functional recovery of the hindlimbs. Markers for neuronal regeneration (Tuj-1, nestin, MAP2, and NF-M), astrogliosis (GALC, GFAP, and pSTAT3), signal molecules for actin cytoskeleton (RhoA, Cdc42, and Rac1), inflammation (COX-2), and neurotrophins (NT-3) were evaluated by Western blot analysis. Scores of the 1-week transplantation group showed significant improvement compared to controls. Hematoxylin and eosin (H&E) staining revealed less fibrosis at the injury site in the 1-week transplantation group compared to other groups and immunohistochemistry showed increased expression of neuronal markers. Furthermore, in both 1-week and 2-week transplantation groups, Tuj-1, nestin, MAP2, NF-M, NT-3, and GFAP increased, but pSTAT3, GALC, and COX2 decreased. RhoA decreased and Rac1 and Cdc42 increased in the 1-week transplantation group. In conclusion, transplantation of cMSCs 1 week after SCI was more effective in improving clinical signs and neuronal regeneration and reducing fibrosis formation compared to the other transplantation times evaluated. Subsequently, these data may contribute to the optimization of timing for MSC transplantation used as a therapeutic modality.Key words: Dog; Stem cells; Optimal transplantation time; Spinal cord injury INTRODUCTIONcomposed of connective tissue elements and glial cells such as astrocytes and oligodendrocytes were thought to explain the failure of central nervous system (CNS) Responses to spinal cord injury (SCI) include disruption of the spinal cord vasculature, ischemia, glutamaterregeneration after injury (6). Oligodendrocytes provide myelin sheaths for enhanced axonal transmission (6), gic excitotoxicity, oxidative cell stress, lipid peroxidation, inflammation, and scar formation (30,51). Inflammation and astrocytes are important for neurotransmitter regulation and ion homeostasis (6,47). But after injury they or scarring as a result of SCI has been found to be detrimental to nerve regeneration (5,6,42). At the site of inare the major cell type responsible for walling off areas of damage to protect normal tissue from further erosion. flammation in the spinal cord, cyclooxygenase-2 (COX2) expression is markedly increased (21,40) and glial cellsIn addition, astrocytes respond to multiple extracellular signaling molecules through a complex assortment of ininteract with inflammator...
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