Prenatal stress differentially alters brain-derived neurotrophic factor expression and signaling across rat strains

Background. Psychiatric illness and anxiety disorders have strong neurodevelopmental components. Environmental insults such as prenatal exposure to stress and genetic differences in stress responses may affect brain development. Methods. A rat model of random variable prenatal stress was used to study the expression and processing of hippocampal brain-derived neurotrophic factor (BDNF) in the offspring of the stressed rat dams. To account for unknown genetic influences that may play a role in the outcome of this prenatal stress paradigm, three different rat strains with known differences in stress responsivity were studied: Fischer, Sprague–Dawley, and Lewis rats (n=132). Results. Multiple disparities in mRNA expression levels of BDNF, and transcripts related to its processing and signaling were found in the three strains. Of the numerous splice variants transcribed from the BDNF gene, the transcript containing BDNF exon VI was most aberrant in the prenatally stressed animals. Protein levels of both uncleaved proBDNF and mature BDNF were also altered, as was intra-cellular signaling by phosphorylation of the neurotrophic tyrosine kinase receptor type 2 (NTRK2, TrkB) and mitogen-activated protein kinase (Erk 1/2). Changes were not only dependent on prenatal stress, but were also strain dependent, demonstrating the importance of genetic background. Conclusion. BDNF signaling provides both positive neurotrophic support for neurons and negative apoptotic effects, both of which may contribute to behavioral or neurochemical outcomes after prenatal exposure to stress. Differential processing of BDNF after prenatal stress in the three rat strains has implications for human subjects where genetic differences may protect or exacerbate the effects of an environmental stressor during fetal development.

▶Six random prenatal stressors were administered to pregnant rat dams of three rat strains, differing in stress response. ▶Total BDNF, proBDNF, and mBDNF mRNA and protein were quantified before and after an acute stressor in brain from offspring. ▶Prenatal stress affected the BDNF response and proBDNF processing to mBDNF in Sprague–Dawley and Lewis rats, but not in Fishers. ▶Processing enzymes were also affected by prenatal stress in Sprague–Dawley and Lewis rats. ▶Results suggest that prenatal stress alters BDNF processing and expression in a strain-specific manner.