Neuroscience
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The mammalian subventricular zone (SVZ) is the largest germinative zone of the adult brain. Progenitor cells generated from the SVZ play important roles during the remyelination process. To determine the functional role of Olig2 in regulating astroglial differentiation in the mouse SVZ, we used the cuprizone mouse model to investigate demyelination. ⋯ Our results indicate that Olig2 may serve as a key regulator during the directional differentiation of progenitor cells after demyelination. The BMP signaling pathway may contribute to the cytoplasmic translocation and altered expression of Olig2 during the remyelination process. These findings provide a better understanding of the mechanisms involved in remyelination.
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Valproic acid (VPA) is a short-chain branched fatty acid with anti-inflammatory, neuro-protective and axon remodeling effects. Here we have studied effects of VPA in gpMBP(68-84)-induced experimental autoimmune encephalomyelitis (EAE). Both preventive (from Day 0 to Day 18) and therapeutic (from Day 7 to Day 18 or from Day 9 to Day 19) VPA (500 mg/kg, intra-gastric) administration to EAE rats once daily greatly reduced the severity and duration of EAE, and suppressed mRNA levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-17, matrix metalloproteinase 9 (MMP9), inducible nitric oxide synthase (iNOS) and transcription factor T-bet, but increased levels of IL-4 mRNA in EAE spinal cords. ⋯ VPA treatment altered the cytokine milieu of lymph nodes, modulating the Th profile from Th1 and Th17 to a profile of Th2 and regulatory T cells. In addition, in vitro study showed that VPA inhibited non-specific lymphocyte proliferation in a dose-dependent manner. In summary, our data demonstrated that VPA could suppress systemic and local inflammation to improve outcome of EAE, suggesting that VPA might be a candidate for treatment of multiple sclerosis.
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Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. ⋯ Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.
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Phosphatase and actin regulators (Phactrs) are a novel family of proteins expressed in the brain, and they exhibit both strong modulatory activity of protein phosphatase 1 and actin-binding activity. Phactrs are comprised of four family members (Phactr1-4), but their detailed expression patterns during embryonic and postnatal development are not well understood. ⋯ Following traumatic brain injury which promotes neurogenesis in the neurogenic region and gliogenesis in the injury penumbra, the mRNA expression of phactr2 and 4 was progressively increased in the injury penumbra, and phactr4 mRNA and protein induction was observed in reactive astrocytes. These differential expression patterns of phactrs imply specific functions for each protein during development, and the importance of Phactr4 in the reactive gliosis following brain injury.
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Neuronal plasticity deficits underlie many of the cognitive problems seen in fetal alcohol spectrum disorders (FASD). We have developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. Recently, we showed that this deficit could be reversed by overexpression of serum response factor (SRF) in the primary visual cortex during the period of monocular deprivation (MD). ⋯ After 24h, these astrocytes were implanted in the visual cortex of alcohol-exposed animals or saline controls one day before MD. Optical imaging of intrinsic signals showed that alcohol-exposed animals that were implanted with astrocytes expressing SRF, but not SRF- or GFP, showed robust restoration of OD plasticity in all visual cortex. These findings suggest that overexpression of SRF exclusively in astrocytes can improve neuronal plasticity in FASD.