xav939 and Demyelinating-Diseases

Adverse early-life experience such as depriving the relationship between parents and children induces permanent phenotypic changes, and impairs the cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanism remains unclear. In this work, we used rat neonatal maternal separation (NMS) model to illuminate whether and how NMS in early life affects cognitive functions, and what the underlying cellular and molecular mechanism is. We showed that rat pups separated from their dam 3 h daily during the first 3 postnatal weeks alters medial prefrontal cortex (mPFC) myelination and impairs mPFC-dependent behaviors. Myelination appears necessary for mPFC-dependent behaviors, as blockade of oligodendrocytes (OLs) differentiation or lysolecithin-induced demyelination, impairs mPFC functions. We further demonstrate that histone deacetylases 1/2 (HDAC1/2) are drastically reduced in NMS rats. Inhibition of HDAC1/2 promotes Wnt activation, which negatively regulates OLs development. Conversely, selective inhibition of Wnt signaling by XAV939 partly rescue myelination arrestment and behavior deficiency caused by NMS. These findings indicate that NMS impairs mPFC cognitive functions, at least in part, through modulation of oligodendrogenesis and myelination. Understanding the mechanism of NMS on mPFC-dependent behaviors is critical for developing pharmacological and psychological interventions for child neglect and abuse.

Topics: Animals; Animals, Newborn; Anxiety; Cognition Disorders; Demyelinating Diseases; Enzyme Inhibitors; Exploratory Behavior; Gene Expression Regulation, Developmental; Heterocyclic Compounds, 3-Ring; Histone Deacetylases; Lipopolysaccharides; Maternal Deprivation; Maze Learning; Myelin Basic Protein; Neurogenesis; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Valproic Acid; Wnt Proteins; Wnt Signaling Pathway

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.

Topics: Adult; Animals; Animals, Newborn; Axin Protein; Basic Helix-Loop-Helix Transcription Factors; beta Catenin; beta-Galactosidase; Brain Injuries; Cell Differentiation; Cells, Cultured; Cerebellum; Cerebral Cortex; Corpus Callosum; Cytoskeletal Proteins; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Heterocyclic Compounds, 3-Ring; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Ki-67 Antigen; Lysophosphatidylcholines; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Multiple Sclerosis; Myelin Proteins; Myelin Sheath; Nerve Tissue Proteins; Neurons; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Organ Culture Techniques; Postmortem Changes; Spinal Cord; Stem Cells; Wnt Proteins