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.

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

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Physical exercise as an epigenetic modulator of brain plasticity and cognition

“…It has been shown that miR-132 alters dendritic morphogenesis by activating the Rac1-PAK pathway (Impey et al, 2010, Wayman et al, 2008) and by regulating MeCP2 expression (Klein et al, 2007, Hansen et al, 2010). More recently, it has been shown that conditional knockout of miR-132/212 gene cluster impairs memory and promotes gross alterations in hippocampal transcriptional profile in mice (Hansen et al, 2016). …”

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“…Given that neuronal communication happens at a much faster rate and is more dynamic than protein biosynthesis, miRNAs could help to adjust protein levels in this ever‐changing environment. However, miRNAs are also found at synapses, where they repress local synaptic translation until neuronal activity requires it . Some miRNAs seem to be directly expressed in response to CREB, highlighting their role in memory formation .…”