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MiR-132 as a Dynamic Regulator of Neuronal Structure and Cognitive Capacity

Hansen, Katelin Libby French
http://orcid.org/0000-0001-7065-0154
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429537435

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
The activity-dependent gene expression observed in the course of neuronal signaling is a central factor mediating functional synaptic plasticity within the central nervous system (CNS). Historically, much of the focus of inducible gene expression has been on protein-coding genes. However, new energy has emerged around the expression of non-protein-coding RNAs following neuronal activity. microRNAs (miRNAs) are small ~22 nucleotide noncoding regulatory molecules involved in the posttranscriptional repression of target mRNAs. miRNAs have emerged as potent mediators of cognitive capacity and hippocampal function, and are implicated in a wide array of neurological disorders. Several miRNA have also been demonstrated to be expressed in an activity-dependent manner within neurons of the CNS. Among them, miR-132 is a neuronally-enriched and robustly-expressed miRNA throughout key regions of the CNS. Along with its sister miRNA miR-212, miR-132 has been demonstrated to be CREB-regulated and activity-inducible in culture. Furthermore, miR-132 is known to regulate dendritic morphogenesis in vitro through p250GAP-mediated Rac1-PAK signaling. Altered expression of miR-132 is associated with a range of neurocognitive disorders, including the autism spectrum disorders, Alzheimer’s disease, Huntington’s disease, and Schizophrenia. Thus, the functional role of miR-132 within nervous system physiology merits close examination. Here, I first present cell-autonomous evidence for the importance of functional miRNA regulation of normal morphogenesis within the excitatory layers of the adult hippocampus (Chapter 2). Then, a Tet-off system is employed to overexpress miR-132 within excitatory forebrain neurons, showing a concordant increase in dendritic spine density and impairment of recognition memory (Chapter 3). Subsequently, this same transgenic system is used to demonstrate that while a robust increase in miR-132 leads to cognitive impairment, moderate increases that parallel levels induced following learning in wildtype animals enhance performance on learning-dependent tasks (Chapter 4). Finally in Chapter 5, using a conditional knockout approach to target deletion of miR-132/212, I report that miR-132 levels must be maintained within a narrow range of expression for functional memory formation and that both increases and decreases in miR-132 transcription lead to cognitive impairment. I also use high-throughput sequencing of RNA isolated from the hippocampi of this conditional knockout model, in conjunction with RNA isolated from animals overexpressing miR-132 and miR-212, to identify newly- predicted mRNAs targets of these miRNAs that may mediate the observed cognitive deficits in these animals. Taken together, these studies reveal miR-132 as a dynamic regulator of activity-dependent synaptic placidity and of cognitive capacity, suggesting significant implications of its regulation within a range of neurocognitive disorders.
Karl Obrietan (Advisor)
Balveen Kaur (Committee Member)
Derick Lindquist (Committee Member)
Thomas Schmittgen (Committee Member)
172 p.
Neurosciences
miRNA; microRNA; miR-132; miR-212; Hippocampus; Learning; Memory; CREB; RNA-seq; high-throughput; sequencing; Dicer;

Recommended Citations

Citations

  • Hansen, K. L. F. (2015). MiR-132 as a Dynamic Regulator of Neuronal Structure and Cognitive Capacity [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429537435

    APA Style (7th edition)

  • Hansen, Katelin. MiR-132 as a Dynamic Regulator of Neuronal Structure and Cognitive Capacity. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429537435.

    MLA Style (8th edition)

  • Hansen, Katelin. "MiR-132 as a Dynamic Regulator of Neuronal Structure and Cognitive Capacity." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429537435

    Chicago Manual of Style (17th edition)

osu1429537435
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