Neuroscience
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Tay-Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage disease caused by a loss of lysosomal hexosaminidase-A (HEXA) activity and characterized by progressive neurodegeneration due to the massive accumulation of GM2 ganglioside in the brain. Here, we generated iPSCs derived from patients with TSD, and found similar potential for neural differentiation between TSD-iPSCs and normal iPSCs, although neural progenitor cells (NPCs) derived from the TSD-iPSCs exhibited enlarged lysosomes and upregulation of the lysosomal marker, LAMP1, caused by the accumulation of GM2 ganglioside. ⋯ TSD-iPSC-derived neurons showed a decrease in exocytotic activity with the accumulation of GM2 ganglioside, suggesting deficient neurotransmission in TSD. Our findings demonstrated that NPCs and mature neurons derived from TSD-iPSCs are potentially useful cellular models of TSD and are useful for investigating the efficacy of drug candidates in the future.
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White matter lesions due to cerebral hypoperfusion may be an important pathophysiology in vascular dementia and stroke, although the inherent mechanisms remain to be fully elucidated. The present study, using a mouse model of chronic cerebral hypoperfusion, examined the white matter protective effects of levetiracetam, an anticonvulsant, via the signaling cascade from the activation of cAMP-responsive element binding protein (CREB) phosphorylation. Mice underwent bilateral common carotid artery stenosis (BCAS), and were separated into the levetiracetam group (injected once only after BCAS [LEV1] or injected on three consecutive days [LEV3]), the vehicle group, or the anti-epileptic drugs with different action mechanisms phenytoin group (PHT3; injected on three consecutive days with the same condition as in LEV3). ⋯ The activation of microglia and astrocytes was markedly suppressed, although the number of oligodendrocyte precursor cells (OPCs) and GST-pi-positive-oligodendrocytes was markedly higher in the cerebral white matter. Moreover, oxidative stress was significantly reduced. We found that 3-day treatment with levetiracetam maintained SV2A protein expression via interaction with astrocytes, which influenced the OPC lineage through activation of CREB to protect white matter from ischemia.
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Substantial evidence has demonstrated that prenatal stress (PS) impairs spatial learning and memory in offspring. The neuron-specific protein kinase C gamma (PKCγ) has been proposed to be unique in spatial learning and memory. The present study proposes to determine whether hippocampal PKCγ is involved in the detrimental effects of PS on spatial learning and memory in offspring, and to further explore the effects of PS-induced PKCγ-dependent growth-associated protein 43 (GAP-43) and neurogranin (Ng) phosphorylation alteration on calcium/calmodulin-dependent protein kinase II (CaMKII) activation. ⋯ Overexpression of PKCγ in the hippocampal CA1 area recovered the ability of spatial learning and memory in PS female offspring. Furthermore, enhancing PKCγ reversed PS-induced membrane and cytosolic PKCγ reduction, and restored levels of GAP-43 and Ng phosphorylation, and CaMKII activation in the hippocampus. In conclusion, PS possibly decreases hippocampal PKCγ activity, resulting in a reduction of p-GAP-43 and p-Ng, which underlies insufficient CaMKII activation, thereby impairing spatial learning and memory.
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Accumulating evidence suggests that glutamatergic signaling and synaptic plasticity underlie one of a number of ways psychiatric disorders appear. The present study reveals a possible mechanism by which this occurs, through highlighting the importance of LMTK3, in the brain. Behavioral analysis of Lmtk3-KO mice revealed a number of abnormalities that have been linked to psychiatric disease such as hyper-sociability, PPI deficits and cognitive dysfunction. ⋯ As synaptic dysfunction is implicated in human psychiatric disease, we analyzed the LTP of Lmtk3-KO mice and found that induction is severely impaired. Further investigation revealed abnormalities in GluA1 trafficking after AMPA stimulation in Lmtk3-KO neurons, along with a reduction in GluA1 expression in the post-synaptic density. Therefore, we hypothesize that LMTK3 is an important factor involved in the trafficking of GluA1 during LTP, and that disruption of this pathway contributes to the appearance of behavior associated with human psychiatric disease in mice.