The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

Abstract

Aging is accompanied by expression changes in multiple genes, and the brain is one of the tissues most vulnerable to aging. Since the α7 nicotinic acetylcholine receptor (nAChR) subunit has been associated with neurodevelopmental disorders and cognitive decline during aging, we hypothesized that its absence might affect gene expression profiles in aged brains. To study whether transcriptional changes occur due to aging, α7 deficiency, or both, we analyzed whole-brain transcriptomes of young (8 weeks) and aged (2 years) α7-deficient and wild-type control mice, using Mouse Genome 430 2.0 microarray. Highly significant expression changes were detected in 47 and 1,543 genes [after Bonferroni and false discovery rate (FDR) correction] in the brains of aged mice compared to young mice, regardless of their genotype. These included genes involved in immune system function and ribosome structure, as well as genes that were previously demonstrated as differentially expressed in aging human brains. Genotype-dependent changes were detected in only three genes, Chrna7 which encodes the α7 nAChR subunit, and two closely linked genes, likely due to a "mouse background effect." Expression changes dependent on age-genotype interaction were detected in 207 genes (with a low significance threshold). Age-dependent differential expression levels were approved in all nine genes that were chosen for validation by real-time RT-PCR. Our results suggest that the robust effect of aging on brain transcription clearly overcomes the almost negligible effect of α7 nAChR subunit deletion and that germ line deficiency of this subunit has a minor effect on brain expression profile in aged mice.

Age-Mediated Transcriptomic Changes in Adult Mouse Substantia Nigra

“…To this end, common changes in gene expression in aged mouse brain were first evaluated by re-analyzing four published microarray studies [26], [44]–[46] using the same method and criteria as in the current study (see Materials and methods ). By comparing the lists of differentially expressed genes from each study using IPA, a “transcriptional signature” of 61 common age-associated genes, which appeared in at least three of the four studies, was generated (supplementary Table S3).…”

“…In order to test this hypothesis, a list of 61 common age-associated genes (transcriptional signature) in ≥ 24 months old mouse brain was first generated (Table S3) and compared with the SNpc data. The transcriptional signature was obtained by re-analyzing four previously published microarray studies of aged mouse brain (whole brain, brain without cerebellum and brain stem, or neocortex) [26], [44]–[46]. A meta-analysis of 4 studies is considered to provide reliable information of common changes during aging, since 3 to 8 studies have been used in similar meta-analyses [25], [26].…”

“…Either whole brain, brain without cerebellum and brain stem, or neocortex was used in each study. Raw microarray data (CEL files) were obtained from public repositories [26], [44], [45] or authors of the study [46]. To avoid the difference in data processing and statistic analysis among studies, these studies were re-analyzed using the same method that was used to analyze the microarray data of SNpc and VTA.…”

Associations between genetic variations and global motion perception

“…Age-related changes in the cholinergic system affect cognition (see Dumas & Newhouse 2011) and visual processing (Ricciardi et al 2009). However, age-related changes are unlikely to be related to variations of a single gene but rather related to complex interactions between multiple genes (Kedmi & Orr-Urtreger 2011). Therefore, further studies are needed to explore interactive effects of multiple genes within the cholinergic system to understand the involvement of the cholinergic system in motion perception with regards to healthy aging.…”

Muscarinic receptor/G-protein coupling is reduced in the dorsomedial striatum of cognitively impaired aged rats

“…Behavioral flexibility is impaired in aged primates (Hara et al, 2011), dogs (Tapp et al, 2003) and rodents (Schoenbaum et al, 2002). Although the neurobiological mechanism underlying the decline in behavioral flexibility in the aged brain is unknown, pharmacological and lesion studies in adult rats indicate that fronto-striatal function is critical.…”