The role of snare proteins in cortical development

Neural communication in the adult nervous system is mediated primarily through chemical synapses, where action potentials elicit Ca2+ signals, which trigger vesicular fusion and neurotransmitter release in the presynaptic compartment. At early stages of development, the brain is shaped by communication via trophic factors and other extracellular signaling, and by contact-mediated cell–cell interactions including chemical synapses. The patterns of early neuronal impulses and spontaneous and regulated neurotransmitter release guide the precise topography of axonal projections and contribute to determining cell survival. The study of the role of specific proteins of the synaptic vesicle release machinery in the establishment, plasticity, and maintenance of neuronal connections during development has only recently become possible, with the advent of mouse models where various members of the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex have been genetically manipulated. We provide an overview of these models, focusing on the role of regulated vesicular release and/or cellular excitability in synaptic assembly, development and maintenance of cortical circuits, cell survival, circuit level excitation–inhibition balance, myelination, refinement, and plasticity of key axonal projections from the cerebral cortex. These models are important for understanding various developmental and psychiatric conditions, and neurodegenerative diseases

Prostaglandin E2 Reverses Aberrant Production of an Inflammatory Chemokine by Microglia from Sandhoff Disease Model Mice through the cAMP-PKA Pathway

Background: Sandhoff disease (SD) is a neurodegenerative lysosomal b-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including terminal GlcNAc-oligosaccharides and GM2 ganglioside. Microglia-mediated neuroinflammation contributes to the pathogenesis and progression of SD. Our previous study demonstrated that MIP-1a, a putative pathogenic factor for SD, is up-regulated in microglial cells derived from SD model mice (SD-Mg) through activation of Akt and JNK. Methodology/Principal Findings: In this study, we first demonstrated that prostaglandin E2 (PGE2), which is one of the lipid mediators derived from arachidonic acid and is known to suppress activation of microglia, reduced the aberrant MIP-1a production by SD-Mg to the same level as by WT-Mg. PGE2 also attenuated the activation of Akt and JNK. The inhibition of MIP-1a production and the activation of Akt and JNK occurred through the EP2 and 4/cAMP/PKA signaling pathway in the murine microglia derived from SD model mice. Conclusions/Significance: We propose that PGE2 plays a role as a negative regulator of MIP-1a production in th

Altered Behavior in Mice with Deletion of the Alpha2-Antiplasmin Gene

<div><p>Background</p><p>The α2-antiplasmin (α2AP) protein is known to be a principal physiological inhibitor of plasmin, and is expressed in various part of the brain, including the hippocampus, cortex, hypothalamus and cerebellum, thus suggesting a potential role for α2AP in brain functions. However, the involvement of α2AP in brain functions is currently unclear.</p><p>Objectives</p><p>The goal of this study was to investigate the effects of the deletion of the α2AP gene on the behavior of mice.</p><p>Methods</p><p>The motor function was examined by the wire hang test and rotarod test. To evaluate the cognitive function, a repeated rotarod test, Y-maze test, Morris water maze test, passive or shuttle avoidance test and fear conditioning test were performed. An open field test, dark/light transition test or tail suspension test was performed to determine the involvement of α2AP in anxiety or depression-like behavior.</p><p>Results and Conclusions</p><p>The α2AP knockout (α2AP^−/−) mice exhibited impaired motor function compared with α2AP^+/+ mice. The α2AP^−/− mice also exhibited impairments in motor learning, working memory, spatial memory and fear conditioning memory. Furthermore, the deletion of α2AP induced anxiety-like behavior, and caused an anti-depression-like effect in tail suspension. Therefore, our findings suggest that α2AP is a crucial mediator of motor function, cognitive function, anxiety-like behavior and depression-like behavior, providing new insights into the role of α2AP in the brain functions.</p></div

Activation of cAMP/PKA reduces MIP-1α production by SD-Mg through dephosphorylation.

<p><b>A</b>: SD-Mg was treated with cAMP analogs, the 6-Bnz-cAMP (PKA-selective; PKA-cA) and 8-pCPT-2′O-Me-cAMP (Epac-selective; Epac-cA) analogs, at 200 µM alone or in combination for 6 h. The amounts of MIP-1α protein in CM were determined by ELISA. Values represent the means ± SD for three independent experiments. **<i>P</i><0.01 versus untreated controls (<i>t</i>-test). <b>B</b>: Cell viability was determined 6 h after treatment with the cAMP analogs. <b>C</b>, <b>D</b>: SD-Mg was treated with 200 µM PKA-selective cAMP for 30 min. Phosphorylation states of Akt and JNK were analyzed by immunoblotting. The histogram on the bottom panels represents the ratio of phorphorylated protein to total protein measured by densitometry. Values represent the means ± SD for three independent experiments. Significance was evaluated by means of Student's <i>t</i>-test. **<i>P</i><0.01 versus WT-Mg.</p

The impaired working memory and spatial memory in α2AP^−/− mice compared with WT mice.

<p>The Y-maze test showed that there was little effect of the α2AP deficiency on the spontaneous behavior of the mice (A), but the working memory was impaired in the α2AP^−/− mice compared with WT mice (B) (WT and α2AP^−/− mice, n = 12 and 8, respectively). The results of the training sessions are shown in C. The number of crossings in each quadrant and the number of crossings over the platform in the probe test are shown in D and E, respectively. The Morris water maze test showed that α2AP^−/− mice exhibited impairments in their spatial memory (C–E) (n = 8). The values represent the means±S.E. Significance was evaluated using Student’s <i>t</i>-test or an ANOVA with a LSD post-hoc test. *P<0.05, **P<0.01.</p

Activation of adenylate cyclase inhibits MIP-1α production by SD-Mg.

<p><b>A</b>: SD-Mg was treated with forskolin, an adenylate cyclase activator, for 6 h at the indicated concentrations. The amounts of MIP-1α protein in CM were determined by ELISA. <b>B</b>: Cell viability was determined 6 h after treatment with forskolin. Values represent the means ± SD obtained for three independent experiments. **<i>P</i><0.01 versus untreated control (<i>t</i>-test).</p