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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Marsillo, Alexandra¹  David, Lovena⁴  Gerges, Bishoy⁴  Kerr, Daniel⁴  Sadek, Rodina⁴  Lasiychuk, Vitaliy⁴  Salame, David⁴  Soliman, Youstina⁴  Menkes, Silvia⁴  Chatterjee, Aheli⁴  Mancuso, Andrew²  Banerjee, Probal^1,3,4 

[1] CUNY Coll Staten Isl, CUNY Doctoral Programs Biol, Staten Isl, NY 10314 USA

[2] CUNY Coll Staten Isl, CUNY Doctoral Programs Biochem, Staten Isl, NY 10314 USA

[3] CUNY Coll Staten Isl, Dept Chem, Staten Isl, NY 10314 USA

[4] CUNY Coll Staten Isl, Ctr Dev Neurosci, Staten Isl, NY 10314 USA

关键词: Fmr1;    PKC epsilon;    GluR2;    Hippocampus;    Hypothalamus;    Oxytocin;   

DOI  :  10.1016/j.bbadis.2020.166048

来源: Elsevier

【 摘 要 】

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 (PKC epsilon) (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 alpha-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 PKC epsilon 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 PKC epsilon 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 PKC epsilon could be a strategy to correct endophenotypic anomalies during brain development and aberrant adult behavior of the FXS males to the wild-type levels.

【 授权许可】

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