Neuroscience
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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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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene. Random X-inactivation produces a mosaic of mutant (MT) and wild-type (WT) neurons in female Mecp2+/- (het) mice. Many RTT symptoms are alleviated by increasing activity in medial prefrontal cortex (mPFC) in RTT model mice (Howell et al., 2017). ⋯ At 6-7 months inhibitory charge in WT in het slices was increased compared to both MT in het and WT in WTf; however, in hets the excitatory/inhibitory charge ratio was still greater in WT compared to MT. nAChR currents were reduced in L6 of nulls and MT L6 in het slices compared to WT neurons of het, WTm and WTf. At 2-4 months, ACh perfusion increased frequency of inhibitory currents to L6 neurons equally in all genotypes but increased excitatory inputs to MT and WT in hets less than WT in WTfs. Unexpectedly ACh perfusion evoked greater sustained IPSC and EPSC input to L5 neurons of nulls compared to WTm.
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The cerebrospinal fluid (CSF) movement and its influence on substance distribution and elimination from the CSF system have been thoroughly analyzed and discussed in the light of the new hypothesis of CSF physiology. As a result, CSF movement is not presented as a circulation, but a permanent rhythmic systolic-diastolic pulsation in all directions. Such movement also represents the main force of substance distribution inside the CSF system. ⋯ If a certain transport mechanism is not available at one site, the substance will be distributed by CSF movement along the CSF system and into the CNS region where that transport mechanism is available. Pharmacological manipulation suggests that the residence time and the substance travel distance along the CSF system depend on the capacity of transport mechanisms situated on CNS blood capillaries. Physiological absorption of the CSF into the venous sinuses and/or lymphatics, due to their small surface area, should be of minor importance in comparison with the huge absorptive surface area of the microvessel network.