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

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.

A Multi-Gene Synaptic Plasticity Array Identifies Candidate Molecular Underpinnings of Cognitive and Mood Deficits in Rats with Heart Failure

“…DH appears to be primarily responsible for the cognitive functions of the hippocampus (Moser & Moser, 1998;Sahay & Hen, 2007;Barkus et al, 2010;Fanselow & Dong, 2010), which is consistent with our finding that that genes associated with learning and memory were only impacted in DH. Our findings also add to evidence suggesting that DH is more vulnerable to neuroinflammation and other pathology than VH (Fuster-Matanzo et al, 2011;Stouffer et al, 2015;Dobryakova et al, 2017;Dobryakova et al, 2019;Tournier et al, 2019).…”

“…Importantly, the PVN is a critical component of the neural circuitry that underlies thirst (Cohn et al, 1984;Krishnan & Nestler, 2011;Dardiotis et al, 2012;Dobryakova et al, 2017) and our PCR gene array findings indicate that HF induces a massive decrease in gene expression in PVN.…”

Saporin from Saponaria officinalis as a Tool for Experimental Research, Modeling, and Therapy in Neuroscience

“…It was found that lesion of BFCN was not associated with changes in mRNA level of the mentioned channels in the frontal cortex [125]. Similarly, MS/DBB and MS/NBM lesions also did not alter mRNA expression of majority of mentioned channels in the hippocampus [126,127]. Presumably, loss of cholinergic afferentation altered translation of some mRNAs but this hypothesis requires further examination.…”

“…Recently, we have applied a transcriptomic approach to study whether 192IgG-saporin induces neuroinflammatory consequences in the hippocampus. Administration of immunotoxin into the cerebral ventricles resulted in moderate impairments of cognitive functions which were associated not only with loss of cholinergic neurons in the medial septum, but also with loss of neurons in the CA3 field of the hippocampus [124,126]. Microglia proliferation was observed in the dorsal hippocampus and in the white matter.…”

“…Microglia proliferation was observed in the dorsal hippocampus and in the white matter. Microglia activation was related to the expression of a subset of genes associated with inflammation specifically in dorsal hippocampus; however, it did not include the genes encoding mediators of acute inflammation, such as IL-1β, IL-6, IL-15, IL-18 or TNFα [126]. Data of transcriptomic analysis were further supported by the results of real-time PCR [124].…”