Repeated variable prenatal stress alters pre- and postsynaptic gene expression in the rat frontal pole.
Exposure of pregnant women to stress during a critical period of fetal brain development is an environmental risk factor for developing schizophrenia in the adult offspring. We have applied a repeated variable stress paradigm to pregnant Sprague-Dawley rats during the last week of gestation coinciding with the second trimester in human brain development. Here we report our findings from a microarray analysis of the frontal pole of the prenatally stressed adult offspring and non-stressed adult controls complemented with measurement of plasma corticosterone levels following exposure to an acute stress. The direction of change of selected genes was confirmed by real time quantitative fluorescence PCR and in situ hybridization. The analysis revealed significant changes in genes associated with the NMDA receptor/postsynaptic density complex and the vesicle exocytosis machinery including NMDA receptor NR1 and NR2A subunits, densin-180, brain enriched guanylate kinase-associated protein, synaptosome-associated protein of 25 kDa, synaphin/complexin and vesicle-associated membrane protein 2/synaptobrevin 2. Interestingly, some of the changes in this animal preparation are analogous to changes observed in schizophrenic and bipolar patients. Our results suggest that application of a repeated variable prenatal stress paradigm during a critical period of fetal brain development reprograms the response of the hypothalamo-pituitary-adrenal axis to acute stress and results in gene expression changes that may have enduring effects on synaptic function in the offspring during adulthood.
Kinnunen
Anu K
AK
Novartis Pharma AG, Nervous System Research, Basel, Switzerland. anu.kinnunen@pharma.novartis.com
Koenig
James I
JI
Bilbe
Graeme
G
D000818:Animals; D001714:Bipolar Disorder / Q000209:etiology; D016000:Cluster Analysis; D003345:Corticosterone / Q000097:blood; D003423:Critical Period, Psychological; D005260:Female; D005625:Frontal Lobe / Q000196:embryology / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D017403:In Situ Hybridization; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000209:etiology; D013312:Stress, Physiological / Q000235:genetics / Q000503:physiopathology*; D013569:Synapses / Q000378:metabolism*
C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D003345:Corticosterone