title: Prenatal stress increased Snk Polo-like kinase 2, SCF β-TrCP ubiquitin ligase and ubiquitination of SPAR in the hippocampus of the offspring at adulthood.
abstract: Exposure to excessive glucocorticoids during fetal development period contributes to later life psychopathology. Prenatal stress decreases dendritic spine density and impair LTP in the hippocampus of rat pups, however, the mechanisms regulating these changes are still unclear. Glutamate receptors are localized in the postsynaptic density. PSD-95 is a postsynaptic scaffolding protein that plays a role in synaptic maturation and regulation of the synaptic strength and plasticity. PSD-95 interacts with other proteins to form the protein networks that promote dendritic spine formation. The present study investigated the effect of prenatal stress on the levels of scaffolding proteins of NMDA receptor in the hippocampus in order to explain how prenatal stress alters the amount of NMDA receptor in the pups' brain. Pregnant rats were randomly assigned to either the prenatal stress (PS) or the control group (C). The pregnant rats in the PS group were restrained in a plexiglas restrainer for 4h/day during the GD 14-21. Control rats were left undisturbed for the duration of their pregnancies. The amount of PSD-95, SPAR, NR2A and NR2B, as well as the levels of Snk Polo-like kinase 2 and the SCF β-TrCP ubiquitin ligase were measured in the hippocampus of the offspring. The results show that prenatal stress induces a reduction in the amount of NR2B and NR2A subunits in the hippocampus of rat pups, parallel to the decrease in PSD-95 and SPAR at P40 and P60. Moreover, prenatal stress increases Snk and β-TrCP in the hippocampus of rat pups, and the timing correlates with the decrease of SPAR and PSD-95. Prenatal stress also induces a significantly increases in the level of ubiquitinated SPAR in the hippocampus of rat pups at adulthood. The results suggest that degradation of SPAR via UPS system may contribute to the loss of PSD-95 and NMDA receptor subunits in the hippocampus of rat pups at adulthood. In conclusion, the present work demonstrates that the developing brain is critically influenced by glucocorticoids, especially during pre- and early postnatal period, which can have long-term effects on brain development. In addition, an involvement of the UPS system in the prenatal stress model has led to a greater understanding of the effects of prenatal stress later on in life.
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, Thailand. Electronic address: nuanchan.chu@mahidol.ac.th.
authors.forename: Naunchan
authors.initials: N
authors.lastname: Chutabhakdikul
authors.forename: Pornprom
authors.initials: P
authors.lastname: Surakul
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism*; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012149:Restraint, Physical / Q000009:adverse effects*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C479629:Sipa1l1 protein, rat; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; D017346:Protein Serine-Threonine Kinases; C530504:Plk2 protein, rat
keywords: Hippocampus; NMDA receptor; PSD-95; Prenatal stress; Serum inducible kinase (Snk); Spine associated RapGAP (SPAR); Ubiquitin proteasome system; β-Tranducin containing protein (β-TrCP)