PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice.

Autor: Marsillo A; CUNY Doctoral Programs in Biology, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., David L; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Gerges B; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Kerr D; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Sadek R; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Lasiychuk V; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Salame D; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Soliman Y; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Menkes S; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Chatterjee A; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Mancuso A; CUNY Doctoral Programs in Biochemistry, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America., Banerjee P; CUNY Doctoral Programs in Biology, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America; Department of Chemistry, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America; Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY 10314-6609, United States of America. Electronic address: probal.banerjee@csi.cuny.edu.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2021 Apr 01; Vol. 1867 (4), pp. 166048. Date of Electronic Publication: 2020 Dec 23.
DOI: 10.1016/j.bbadis.2020.166048
Abstrakt: Fragile X Syndrome (FXS) is an inherited developmental disorder caused by the non-expression of the Fmr1 gene. FXS is associated with abnormal social and anxiety behavior that is more prominent among males. Given that oxytocin (OXT) regulates both social and anxiety behavior, we studied the effect of FXS in the hypothalamic paraventricular nucleus (PVN), the major central source of OXT. We observed a significant suppression of protein kinase C epsilon (PKCε) (34%) in the ventral hippocampal CA1 region of postnatal day-18 (P18) male Fmr1 knockout (KO) mice, which displayed social behavior deficits and hyper-anxiety in adulthood. These mice also displayed a 39% increase in cell surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) at P18 (measured by the surface level of the AMPAR subunit GluR2), thereby indicating excitation of the CA1 neurons. It is known that neuronal activation at CA1 is linked to an inhibition of the PVN neurons. As expected, these mice also displayed a 25% suppression of oxytocin+ (OXT+) cells in the PVN at P20. Stimulating PKCε during postnatal days 6-,14 (P6-14) mice using a selective activator, dicyclopropyl-linoleic acid (DCP-LA), corrected AMPAR externalization in CA1 and suppression of OXT+ cell number in PVN in a PKCε dependent manner. Most notably, neonatal DCP-LA treatment rescued social behavior deficits and hyper-anxiety, displayed by adult (≥P60) male but not female KO mice. Thus, neonatal stimulation of PKCε could be a strategy to correct endophenotypic anomalies during brain development and aberrant adult behavior of the FXS males to the wild-type levels.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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