title: Chronic corticosterone exposure alters postsynaptic protein levels of PSD-95, NR1, and synaptopodin in the mouse brain.
abstract: Animal models provide compelling evidence that chronic stress is associated with biochemical and morphological changes in the brain, many of which are mediated by corticosterone, a principal glucocorticoid synthesized in the rodent adrenal cortex and secreted in response to stress. To better characterize the effects of chronic corticosterone at the synaptic and subsynaptic level, we implanted three-month-old male C57B/6 mice with 2 × 5 mg corticosterone pellets (CORT group, n = 14), 21 day release formulation (20 mg/kg/day dose) or placebo pellets (Placebo group, n = 14), 21-day release formulation. After 20 days, brains were removed. One hemisphere was frozen for biochemical analysis by synaptosomal fractionation with Western blotting, and the other hemisphere was fixed for immunohistochemistry. Localization and expression levels for PSD-95, NR1, and synaptopodin proteins were assessed. Biochemical analysis revealed lower protein levels of PSD-95 (32% decrease, P < 0.001), NR1 (47%, P = 0.01), and synaptopodin (65%, P < 0.001) in the postsynaptic density subsynaptic fraction of the CORT group. Optical densitometry in immunohistochemically labeled sections also found lower levels of PSD-95 in synaptic fields of the dentate gyrus (PSD-95, 33% decrease, P < 0.001; NR1, 31%, P < 0.001; synaptopodin, 40%, P < 0.001) and the CA3 stratum lucidum (36%, P < 0.001, 40%, P < 0.001, and 35%, P < 0.001) of the CORT group. While mechanistic relationships for these changes are not yet known, we speculate that synaptopodin, which is involved in regulation of spine calcium kinetics and posttranslational modification and transport of locally synthesized proteins, may play an important role in the changes of PSD-95 and NR1 protein levels and other synaptic alterations.
authors.affiliation: Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Julia W
authors.initials: JW
authors.lastname: Cohen
authors.forename: Natalia
authors.initials: N
authors.lastname: Louneva
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Han
authors.forename: Georgia E
authors.initials: GE
authors.lastname: Hodes
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wilson
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Irwin
authors.initials: I
authors.lastname: Lucki
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D003345:Corticosterone / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C503968:Synpo protein, mouse; D051528:Guanylate Kinases; D003345:Corticosterone