miRNA-132’s Role as a Dynamic Regulator of Memory
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Date
2012-02
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Brain Structure and Function
Abstract
Background:
MicroRNAs (miRNAs) are small, evolutionarily conserved, molecules that act as potent silencers of gene expression via translational repression and/or mRNA destabilization. Recent work has shown they can be expressed neuronally in an activity-dependent manner. Within this context, particular attention has been paid to miRNA-132 (miR-132). miR-132 has been shown to increase dendritic growth and spinogenesis in cultured hippocampal neurons and in brain slices. Furthermore, selective deletion of the miR-132/212 locus leads to significant alterations in neuronal morphology in new-born adult hippocampal neurons, including decreased dendritic complexity and spine density. miR-132 has been implicated in multiple neurocognitive disorders characterized by dysregulated synaptogenesis, including Rett Syndrome, Schizophrenia, and Alzheimer’s Disease. Thus, miR-132 appears to be well-positioned to couple synaptic activity to neuronal structural/functional plasticity.
Research Method:
Endogenous miR-132 expression: Wild-type (WT) animals were exposed to two days of Barnes maze learning (adapted from Sunyer et al., 2007). To assess the subsequent levels of miRNA induction, fluorescent in situ hybridization (FISH) against miRNA132 was performed by hybridization with a locked nucleic acid (LNA) anti-miR132 probe. Intensity of expression was measured relative to control animals.
Transgenic miR-132 expression: To further investigate miR-132 function, we generated a tetracycline regulated bi-directional pBI-G vector that drives the expression of premiR132 and a cyan fluorescent marker protein (CFP). This vector was then used to make a miR-132 transgenic mouse line. Transgene expression was driven by crossing the miR-132 animals with the CaMKII tTA driver line.
Doxycycline transgene regulation: Transgenic expression of miR-132 was titered by varying the concentration of doxycycline administered through the drinking water to tTA::miR132 animals. The miR-132 expression observed by FISH in WT animals after learning was used as a reference point for dynamic expression in TA::miR132 mice.
Learning paradigm: Cognitive capacity of the tTA::miR132 mice was assessed by novel object recognition (Bevins and Besheer, 2006) and Barnes maze performance (Sunyer et al., 2007). Neuronal morphology analysis was performed by crossing the tTA::miR132 mouse line with a Thy1-GFP transgene mouse line. The GFP transgene allows for clear visualization of hippocampal neuronal ultrastructure.
Findings: miR-132 is expressed throughout the excitatory sublayers of the WT hippocampus, and was induced ~1.5 fold in the CA1, CA3, and granule cell layers after learning. Using the transgenic tTA::miR132 mouse line to vary miR-132 expression within these layers, moderate (~1.5 fold) increases in transgenic miR-132 (matching levels induced after learning in WT animals) resulted in enhanced cognitive capacity relative to nontransgenic littermates. However, robust miR-132 over-expression (~4 fold), paralleling levels of miR-132 induction after seizure activity, resulted in significant deficits in memory-dependant tasks. Further, this dose-dependent cognitive phenotype of transgenic miR-132 was accompanied by similar changes in neuronal morphology (i.e., spine density) within the hippocampus.
Implications There appears to be narrow, optimized range of miR-132 expression that enhances and facilitates learning and memory formation. However, deviation from this range results in impaired cognition. These findings reveal a critical role for miR-132 in the network of neuronal cellular signaling events that underlie hippocampal-dependent learning and memory. A more complete understanding the role of miR-132 in cognition could provide new insights into the etiology of an array of neurocognitive disorders.
Description
Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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Citation
In review: Hansen et al. miRNA-132: a dynamic regulator of cognitive capacity. Brain Structure and Function.