title: Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome.
abstract: miR-132 and miR-212 are structurally related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same noncoding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/-212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/-212 double-knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/-212 double-knockout line to explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/-212 deletion increased the expression of 1138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/-212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that these two genes may function in a complex, nonredundant manner to shape the transcriptional profile of the CNS. The dysregulation of miR-132/-212 expression could contribute to signaling mechanisms that are involved in an array of cognitive disorders.
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Katelin F
authors.initials: KF
authors.lastname: Hansen
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Aten
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Kaiden H
authors.initials: KH
authors.lastname: Price
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Loeser
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Hesse
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Chloe E
authors.initials: CE
authors.lastname: Page
authors.affiliation: Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.affiliation: College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.affiliation: Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA obrietan.1@osu.edu.
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism*; D021641:Recognition, Psychology / Q000502:physiology; D065852:Spatial Memory / Q000502:physiology; D050827:Syntaxin 1 / Q000378:metabolism; D059467:Transcriptome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D050827:Syntaxin 1; C499317:Ascl1 protein, mouse; C546976:MIRN132 microRNA, mouse; C554518:MIRN212 microRNA, mouse; C494214:Stx1a protein, mouse