Neuroscience
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In the present study we examined the effects of normal aging in the hippocampus and cerebellum, as well as behaviors associated with these substrates. A total of 67 CB6F1 hybrid mice were tested at one of five ages (4, 8, 12, 18 or 25 months) on the context pre-exposure facilitation effect (CPFE) modification of fear conditioning, rotorod, Barnes maze, acoustic startle, Morris water maze (MWM) and 500-ms trace eyeblink classical conditioning (EBCC). Behavioral tasks were chosen to increase the ability to detect age-related changes in learning, as trace EBCC is considered a more difficult paradigm (compared to delay EBCC) and the CPFE has been found to be more sensitive to hippocampus insults than standard contextual fear conditioning. ⋯ Although the CPFE task is considered more sensitive to hippocampus insult, no age-related impairment was found. Spatial memory retention was impaired in the Barnes maze at 25 months, but no significant deficits were seen in the MWM. These results support the finding of differential aging in the hippocampus and cerebellum.
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Theiler's murine encephalomyelitis virus (TMEV) induces demyelination in susceptible strains of mice through a CD4(+) Th1 T cell-mediated immunopathological process. TMEV infection produces a syndrome in mice that resembles multiple sclerosis. In this work, we focused on the increased expression of the genes encoding voltage-gated Ca(2+) channel subunits in SJL/J mouse astrocytes infected in culture with a BeAn strain of TMEV. ⋯ TMEV infection in mouse astrocytes induced a Ca(2+) current with a density proportional to the amount of viral particles used for infection. The use of Ca(2+) channel blockers, nimodipine and ω-conotoxin-GVIA, showed that both functional L- and N-type Ca(2+) channels were upregulated in infected astrocytes. The upregulation of Ca(2+) channels in astrocytes after TMEV infection provides insight into the molecular processes and potential role of astrocyte Ca(2+) dysregulation in the pathophysiology of encephalomyelitis and is important for the development of novel therapeutic strategies leading to prevention of neurodegeneration.
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Adult neurogenesis occurs throughout life; however the majority of new neurons do not survive. Enhancing the survival of these new neurons will increase the likelihood that these neurons could return function following injury. Inhibition of Rho kinase is known to increase neurite outgrowth and regeneration. ⋯ These mice also demonstrated enhanced spatial memory as tested by the Y maze with no significant changes in anxiety or novel object recognition. Rho kinase inhibition enhanced the survival of new born neurons in the dentate gyrus with a specific dosage effect. These results suggest that inhibition of Rho kinase following injury could be beneficial for increasing the survival of new neurons that may aid recovery.
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Various protein motifs play a key role in regulating protein biogenesis and trafficking. Here, we discovered that three distinct motifs regulate the trafficking of acid-sensing ion channel 1a (ASIC1a), the primary neuronal proton receptor which plays critical roles in neurological diseases including stroke, multiple sclerosis and seizures. Mutating the PDZ binding motif of ASIC1a increased its surface expression and current density. ⋯ These changes were likely due to a change in ASIC1a biogenesis; mutating either the RRGK or KEAKR motif reduced N-glycosylation of ASIC1a while mutating the PDZ binding motif had the opposite effect. Our results demonstrate that these C-terminal motifs are important for ASIC1a trafficking and channel function. In addition, in contrast to multiple previous studies, which all show that K/R containing motifs lead to endoplasmic reticulum (ER) retention, our findings indicate that these motifs can also be required for efficient trafficking.
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Increasing evidence has linked membrane cholesterol to amyloid precursor protein (APP) processing. β-Sitosterol (BS) is one of the most common forms of plant sterols, with the structure very similar to that of cholesterol. Using HT22 mouse hippocampal cells, this study investigated whether the substitution of membrane cholesterol with BS influences APP metabolism. ⋯ Additional experiments suggest that the effect of membrane BS on APP metabolism is associated with the migration of APP from lipid rafts toward non-raft regions. Given that dietary BS can enter the brain and accumulates in the plasma membrane of brain cells, these results suggest a potential use of BS in the prevention of Alzheimer's disease.