Effects of early neonatal proinflammatory stress on the expression of BDNF transcripts in the brain regions of prepubertal male rats

Early postnatal proinflammatory stress provokes behavioral impairments in adulthood; however, underlying mechanisms are still elusive. Brain-derived neurotrophic factor (BDNF) plays a crucial role in neuroplastic changes in health as well as at pathology. The BDNF gene is transcribed to exon-specific mRNAs and the pattern of their expression depends on stimulus. We suggest that disturbances of exonspecific BDNF mRNA expression in the brain regions after stress induced by proinflammatory stimuli in early postnatal period could be one of the underlying mechanisms of consequent behavioral impairments. Thus, the aim of the study was to investigate the effects of proinflammatory stress in early postnatal ontogeny on the expression of BDNF and the patterns of expression of the BDNF gene in the neocortex and hippocampus of prepubertal male rats. The proinflammatory stress was induced by subcutaneous administration of bacterial lipopolysaccharide (LPS) to rat pups on postnatal days 3 and 5, while BDNF expression was analyzed in 36-day-old rats. BDNF polypeptide concentration was estimated by means of an enzyme-linked immunosorbent assay, while quantitative polymerase chain reaction followed by reverse transcription was used to detect exon-specific BDNF mRNA expression. The levels of BDNF and transcripts, containing common exon IX were similar in the control and LPS-treated rats. In the rats treated with LPS, the level of BDNF mRNA, containing exon IV, was lower in the neocortex, but not in the hippocampus. No changes in the expression of the transcripts containing exons I and VI were observed in any brain structure studied. We suggest that specific alterations in BDNF expression may be involved in the susceptibility to the development of behavioral impairments of animals subjected to early proinflammatory stress

Intracerebroventricular Administration of 192IgG-Saporin Alters Expression of Microglia-Associated Genes in the Dorsal But Not Ventral Hippocampus

One of important aspects of development of Alzheimer’s disease is degeneration of septal cholinergic neurons that innervate the hippocampus. We took advantage of widely used model of cholinergic deficit in the hippocampus, intracerebroventricular administration of 192IgG-saporin (Ig-saporin), to analyze the postponed consequences of cholinergic deficit in different parts of the hippocampus. We studied effects of the immunotoxin on the behavior of rats and gene expression in the dorsal and ventral hippocampus using RNA-seq approach. We found that under normal conditions dorsal and ventral parts of the hippocampus differ in the expression of 1129 protein-coding genes and 49 non-coding RNAs (ncRNAs) and do not differ in the expression of 10 microRNAs, which were detected in both parts of the hippocampus. Ig-saporin-induced degeneration of cholinergic septal neurons did not affect rat behavior in open field, T-maze, and passive avoidance task but impaired memory retention in Morris water maze. To analyze 192Ig-saporin-induced changes in the gene expression, we formed the following groups of genes: genes expressed exclusively in certain cell types (neurons, astrocytes, microglia, oligodendrocytes, and vascular cells) and, among universally expressed genes, a group of genes that encode ribosome-forming proteins. For all groups of genes, the alterations in the gene expression produced by the immunotoxin were stronger in the dorsal as compared to the ventral hippocampus. We found that, among groups of universally expressed genes, Ig-saporin increased the expression of ribosome-forming proteins in both dorsal and ventral hippocampus. Ig-saporin also strongly upregulated expression of microglia-specific genes only in the dorsal hippocampus. A subset of affected microglial genes comprised genes associated with inflammation, however, did not include genes related to acute inflammation such as interleukins-1b, -6, -15, and -18 as well as TNF. The expression of other cell-specific genes (genes specific for neurons, astrocytes, oligodendrocytes, and vascular cells) was unaffected. The data obtained suggest that disturbance of memory-associated behavior after administration of Ig-saporin is associated with upregulation of microglia-associated genes in the dorsal but not ventral hippocampus