Effect of hydrocephalus on rat brain extracellular compartment

<p>Abstract</p> <p>Background</p> <p>The cerebral cortex may be compressed in hydrocephalus and some experiments suggest that movement of extracellular substances through the cortex is impaired. We hypothesized that the extracellular compartment is reduced in size and that the composition of the extracellular compartment changes in rat brains with kaolin-induced hydrocephalus.</p> <p>Methods</p> <p>We studied neonatal (newborn) onset hydrocephalus for 1 or 3 weeks, juvenile (3 weeks) onset hydrocephalus for 3–4 weeks or 9 months, and young adult (10 weeks) onset hydrocephalus for 2 weeks, after kaolin injection. Freeze substitution electron microscopy was used to measure the size of the extracellular compartment. Western blotting and immunohistochemistry with quantitative image densitometry was used to study the extracellular matrix constituents, phosphacan, neurocan, NG2, decorin, biglycan, and laminin.</p> <p>Results</p> <p>The extracellular space in cortical layer 1 was reduced significantly from 16.5 to 9.6% in adult rats with 2 weeks duration hydrocephalus. Western blot and immunohistochemistry showed that neurocan increased only in the periventricular white matter following neonatal induction and 3 weeks duration hydrocephalus. The same rats showed mild decorin increases in white matter and around cortical neurons. Juvenile and adult onset hydrocephalus was associated with no significant changes.</p> <p>Conclusion</p> <p>We conclude that compositional changes in the extracellular compartment are negligible in cerebral cortex of hydrocephalic rats at various ages. Therefore, the functional change related to extracellular fluid flow should be reversible.</p

In control rats, the cerebral cortex (A) and white matter (C) exhibit minimal immunoreactivity

In age matched hydrocephalic rats, perineuronal labeling is increased in the cerebral cortex (B) and periglial labeling is increased in the white matter (E). No labeling is seen in hydrocephalic white matter when the primary antibody is omitted (D). Scale bar = 100 μm. The bar graph shows densitometric analysis of immunolabeling (arbitrary units) in cortex layer 1 of control (C) and hydrocephalic (H) rats. The hydrocephalus-related increase is significant only in the 3-week rats (*= 0.0003 ANOVA, Bonferroni-Dunn; all groups n = 4). Note that significant changes were also present in the glia limitans.<p><b>Copyright information:</b></p><p>Taken from "Effect of hydrocephalus on rat brain extracellular compartment"</p><p>http://www.cerebrospinalfluidresearch.com/content/5/1/12</p><p>Cerebrospinal Fluid Research 2008;5():12-12.</p><p>Published online 10 Jul 2008</p><p>PMCID:PMC2488327.</p><p></p

The upper two are the original micrographs and the lower two show the extracellular compartment highlighted in red

Note that the hydrocephalic brain has reduced extracellular space. Scale bar = 0.2 μm<p><b>Copyright information:</b></p><p>Taken from "Effect of hydrocephalus on rat brain extracellular compartment"</p><p>http://www.cerebrospinalfluidresearch.com/content/5/1/12</p><p>Cerebrospinal Fluid Research 2008;5():12-12.</p><p>Published online 10 Jul 2008</p><p>PMCID:PMC2488327.</p><p></p

Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4)

A survey of PDE4 inhibitors reveals that some compounds trigger intracellular aggregation of PDE4A4 into accretion foci through association with the ubiquitin-binding scaffold protein p62 (SQSTM1). We show that this effect is driven by inhibitor occupancy of the catalytic pocket and stabilization of a “capped state” in which a sequence within the enzyme’s upstream conserved region 2 (UCR2) module folds across the catalytic pocket. Only certain inhibitors cause PDE4A4 foci formation, and the structural features responsible for driving the process are defined. Switching to the UCR2-capped state induces conformational transition in the enzyme’s regulatory N-terminal portion, facilitating protein association events responsible for reversible aggregate assembly. PDE4-selective inhibitors able to trigger relocalization of PDE4A4 into foci can therefore be expected to exert actions on cells that extend beyond simple inhibition of PDE4 catalytic activity and that may arise from reconfiguring the enzyme’s protein association partnerships

ILC Reference Design Report Volume 1 - Executive Summary

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization