Neuroscience
-
Calcineurin (PP2B) is a Ca(2+)-dependent protein phosphatase enriched in the brain that takes part in intracellular signaling pathways regulating synaptic plasticity and neuronal functions. Calcineurin-dependent pathways are important for complex brain functions such as learning and memory. More recently, they have been suggested to play a role in the processing of emotional information. ⋯ We observed that CN98 mice are more sensitive to the behavioral effect of fluoxetine and desipramine tested in the tail suspension test. Moreover, the basal expression of growth factor brain-derived neurotrophic factor and subunit 1 of AMPA glutamate receptor, GluR1, both of which are modified after chronic antidepressant administration, are altered in the hippocampus of CN98 mice. These results suggest that calcineurin-dependent dephosphorylation plays an important role in the mechanisms of action of antidepressants, providing a new starting point for developing improved therapeutic treatments for depression.
-
We investigated the effect of a single administration of recombinant human erythropoietin (rhEPO) on the preservation of the ventral white matter of rats at 4 weeks after contusive spinal cord injury (SCI), a time at which functional recovery is significantly improved in comparison to the controls [Gorio A, Necati Gokmen N, Erbayraktar S, Yilmaz O, Madaschi L, Cichetti C, Di Giulio AM, Enver Vardar E, Cerami A, Brines M (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99:9450-9455; Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 102:16379-16384]. ⋯ Sparing of fiber tracts in the ventral white matter was confirmed by the increased density of the serotonergic plexus around motor neurons. As for chondroitin sulfate proteoglycans, only phosphacan, increased in saline-treated rats, returned to normal levels in rhEPO group, probably reflecting a better maintenance of glial-axolemmal relationships along nerve fibers. In conclusion, this investigation expands previous studies supporting the pleiotropic neuroprotective effect of rhEPO on secondary degenerative response and its therapeutic potential for the treatment of SCI and confirms that the preservation of the ventral white matter, which contains descending motor pathways, may be critical for limiting functional deficit.
-
Vaccination with Abeta(1-42) and treatment with NCX-2216, a novel nitric oxide releasing flurbiprofen derivative, have each been shown separately to reduce amyloid deposition in transgenic mice and have been suggested as potential therapies for Alzheimer's disease. In the current study we treated doubly transgenic amyloid precursor protein and presenilin-1 (APP+PS1) mice with Abeta(1-42) vaccination, NCX-2216 or both drugs simultaneously for 9 months. We found that all treatments reduced amyloid deposition, both compact and diffuse, to the same extent while only vaccinated animals, with or without nonsteroidal anti-inflammatory drug (NSAID) treatment, showed increased microglial activation associated with the remaining amyloid deposits. ⋯ This is the first report showing that active immunization can result in increased vascular amyloid and microhemorrhage, as has been observed with passive immunization. Co-administration of an NSAID agent with Abeta vaccination does not substantially modify the effects of Abeta immunotherapy. The difference between these treatments with respect to vascular amyloid development may reflect the clearance-promoting actions of the vaccine as opposed to the production-modifying effects proposed for flurbiprofen.
-
Sensory information in the retina is transferred from rod and cone photoreceptors to higher visual centers via numerous parallel circuits that sample the photoreceptor mosaic independently. Each circuit consists of a unique combination of ganglion cell, bipolar and amacrine cell types. The morphology and physiological responses of many amacrine cells have been characterized. ⋯ The best-labeled GFP-expressing cell type in the INL was a wide-field amacrine cell that ramified in stratum 3. The GFP-expressing cells in the GCL resemble the type B1, or possibly A2 ganglion cells. The CD44-EGFP mice should provide a valuable resource for electrophysiological and connectivity studies of amacrine cells in the mouse retina.
-
The proinflammatory and potential neurotoxic cytokine tumor necrosis factor (TNF) is produced by activated CNS resident microglia and infiltrating blood-borne macrophages in infarct and peri-infarct areas following induction of focal cerebral ischemia. Here, we investigated the expression of the TNF receptors, TNF-p55R and TNF-p75R, from 1 to 10 days following permanent occlusion of the middle cerebral artery in mice. Using quantitative polymerase chain reaction (PCR), we observed that the relative level of TNF-p55R mRNA was significantly increased at 1-2 days and TNF-p75R mRNA was significantly increased at 1-10 days following arterial occlusion, reaching peak values at 5 days, when microglial-macrophage CD11b mRNA expression was also increased. ⋯ In situ hybridization revealed mRNA expression of both receptors in predominantly microglial- and macrophage-like cells in the peri-infarct and subsequently in the infarct, and being most marked from 1 to 5 days. Using green fluorescent protein-bone marrow chimeric mice, we confirmed that TNF-p75R was expressed in resident microglia and blood-borne macrophages located in the peri-infarct and infarct 1 and 5 days after arterial occlusion, which was supported by Western blotting. The data show that increased expression of the TNF-p75 receptor following induction of focal cerebral ischemia in mice can be attributed to expression in activated microglial cells and blood-borne macrophages.