Abstract
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.
Highlights
Alzheimer’s disease (AD) is a devastating disease which strongly reduces cognitive abilities
The animals from the immunotoxin-treated group exhibited a strong trend to swim longer distance to reach the platform as compared to the control group, and this distance decreased during the training period in both groups studied (F8,112 = 20.5, P < 0.001) (Figure 1B)
According to our behavioral data, analysis of gene expression was performed in rats with moderate impairments of learning and memory
Summary
Alzheimer’s disease (AD) is a devastating disease which strongly reduces cognitive abilities. It was shown that AD causes strong alterations in the expression of genes (Tan et al, 2010; Berchtold et al, 2014; Wang et al, 2016) but the key factors that induce these changes are not clear. Another important event that occurs in AD is degeneration of cholinergic neurons in the basal nuclei including septal neurons that form inputs to the hippocampus (Francis et al, 1999). To analyze consequences of cholinergic deficit in the hippocampus at the mRNA level, we used a well-described model of induction of cholinergic deficit in the hippocampus – intracerebroventricular (i.c.v.) injection of immunotoxin 192IgG-saporin (Ig-saporin) which causes selective degeneration of cholinergic neurons in the septum and DBB (Heckers et al, 1994)
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