Region‐specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6‐AP ubiquitin protein ligase Ube3a (Ube3a^m?/p+), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum‐dependent task. We used whole‐cell patch‐clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a^m?/p+ mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild‐type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a^m?/p+ mice were more habitual, impervious to changes in outcome value and action–outcome contingency. In the DMS, but not the DLS, Ube3a^m?/p+ mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.     

Collapsin response‐mediator protein 5 (CRMP5) phosphorylation at threonine 516 regulates neurite outgrowth inhibition

The collapsin response‐mediator proteins (CRMPs) are multifunctional proteins highly expressed during brain development but down‐regulated in the adult brain. They are involved in axon guidance and neurite outgrowth signalling. Among these, the intensively studied CRMP2 has been identified as an important actor in axon outgrowth, this activity being correlated with the reorganisation of cytoskeletal proteins via the phosphorylation state of CRMP2. Another member, CRMP5, restricts the growth‐promotional effects of CRMP2 by inhibiting dendrite outgrowth at early developmental stages. This inhibition occurs when CRMP5 binds to tubulin and the microtubule‐associated protein MAP2, but the role of CRMP5 phosphorylation is still unknown. Here, we have studied the role of CRMP5 phosphorylation by mutational analysis. Using non‐phosphorylatable truncated constructs of CRMP5 we have demonstrated that, among the four previously identified CRMP5 phosphorylation sites (T509, T514, T516 and S534), only the phosphorylation at T516 residue was needed for neurite outgrowth inhibition in PC12 cells and in cultured C57BL/6J mouse hippocampal neurons. Indeed, the expression of the CRMP5 non‐phosphorylated form induced a loss of function of CRMP5 and the mutant mimicking the phosphorylated form induced the growth inhibition function seen in wildtype CRMP5. The T516 phosphorylation was achieved by the glycogen synthase kinase‐3β (GSK‐3β), which can phosphorylate the wildtype protein but not the non‐phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin‐binding property of CRMP5. Therefore, CRMP5‐induced growth inhibition is dependent on T516 phosphorylation through the GSK‐3β pathway. The findings provide new insights into the mechanisms underlying neurite outgrowth.     

3升塑料袋用于腹腔扩容治疗腹内高压症

【摘要】〓目的〓探讨3升塑料袋腹腔扩容在腹腔高压症中的应用。方法〓18例腹腔高压症的患者,包括急性重症胰腺炎、肠系膜血管栓塞、消化道穿孔、肠扭转及腹部外伤的危重症患者。所有患者均性剖腹探查手术及采用3升塑料袋腹腔扩容、减压,4~8天患者平稳后二次手术。 结果〓18例患者中死亡3例,其中急性重症胰腺炎1例,全小肠扭转1例,消化道穿孔1例,另15例痊愈出院。术后并发症包括2例腹腔脓肿、1例切口疝、1例出现营养吸收不良。 结论〓3升塑料袋腹腔扩容在腹腔高压症中的应用安全、经济、疗效满意。