Abnormalities in dendritic spines have long been associated with cognitive dysfunction and neurodevelopmental delay, whereas rapid changes in spine shape underlie synaptic plasticity. The key regulators of cytoskeletal reorganization in dendrites and spines are the Rho GTPases, which modify actin polymerization in response to synaptic signaling. Rho GTPase activity is modulated by multiple regulatory proteins, some of which have been found to associate with proteins localized to spines. Here, we show that the nonkinase phorbol ester receptor ␣1-chimerin is present in dendrites and spines, where it binds to the NMDA receptor NR2A subunit in a phorbol ester-dependent manner. ␣1-Chimerin contains a GTPase activating (GAP) domain, with activity toward the Rho family member Rac1. Overexpression of ␣1-chimerin in cultured hippocampal neurons inhibits formation of new spines and removes existing spines. This reduction in spine density is mediated by Rac1 inhibition, because it depends critically on the presence of a functional GAP domain. Conversely, depletion of ␣1-chimerin leads to an increase in spine density, indicating that a basal inhibition of Rac1 maintains the number of spines at a submaximal level. The ability of ␣1-chimerin to modulate spine number requires an interaction with the NMDA receptor, because an ␣1-chimerin mutant that binds weakly to NR2A fails to decrease spine density. Together, these results suggest that ␣1-chimerin is able to modulate dendritic spine morphology by binding to synaptic NMDA receptors and locally inactivating Rac1.

Tetraheptylammonium salts of various transition-metal-substituted heteropolyanions with alpha-Keggin ([XW(11)O(39)M](n)()(-)), alpha-Wells-Dawson ([P(2)W(17)O(61)M](m)(-)), and Weakley and Finke structures ([P(2)W(18)O(68)Co(4)](10)(-)) were investigated with respect to their reactivity with CO(2) in nonpolar solvents. It was found that copper(II)- and manganese(III)-substituted heteropolyanions do not react with CO(2). Germano- and silicotungstates with the alpha-Keggin structure do form complexes with CO(2) when substituted with Co(II), Ni(II), and Mn(II). In contrast, boro- and phosphotungstates substituted with Co(II), Ni(II), and Mn(II) are unreactive. The alpha(2) isomers of Wells-Dawson phosphotungstates show reactivity similar to that of alpha-Keggin silicotungstates-i.e., Co(II), Ni(II), and Mn(II) derivatives do react with CO(2). On the other hand, the alpha(1) isomer of the Co(II)-substituted Wells-Dawson anion does not react with CO(2), and neither does the Weakley and Finke cobaltotungstate. When reactions do occur, they are completely reversible. An excess of water decomposes the complexes. Traces of water are, however, necessary for the reactions to take place. The CO(2) adducts were characterized by UV/vis, IR, and (13)C NMR. The IR data could be explained as originating either from CO(2) complexes with a direct eta(1) metal-carbon bond or from bicarbonato complexes. IR spectra with isotopically enriched (13)CO(2) and C(18)O(2) support the presence of a eta(1) metal-carbon bond. The (13)C NMR spectra indicate the presence of two different kinds of paramagnetic CO(2) complexes after the reaction of alpha-[SiW(11)O(39)Co](6)(-) with CO(2) (chemical shifts 792 and 596 ppm at 26 degrees C). The variable-temperature experiments are consistent with the chemical exchange between these two species. UV/vis, IR, and NMR studies in the presence of controlled amounts of water or ethanol suggest the existence of H-bonding in the CO(2) complexes, similar to that reported in the past for complexes between heteropolyanions and dioxygen.

Here, we discuss the causes of CPSP and current useful preventive strategies in the perioperative period. We also discuss future potential disease-modifying treatments of CPSP.