Micro-RNA Dependent Regulation of Synaptic Plasticity and Associated Cognition Dysfunction in Aging Mouse Hippocampal Neurons

Abstract

Aging is often accompanied by cognitive decline, a critical public health issue in our rapidly aging society. Identification of underlying mechanisms may lead to treatments that slow the progression of age-dependent cognitive deficits. MicroRNAs (miRNAs) are important regulators of neuronal protein expression. Hippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. In my dissertation, I examined if miRNAs contribute to this age-associated decline in hippocampal function by employing bio-informatics and molecular genetics approach in C57BL/6J mouse. By performing miRNA expression profiling and pathway prediction of putative target genes, I found that key upregulated miRNAs are involved in the regulation of hippocampal synaptic function and associated cognition dysfunction. In particular, I focused my thesis on two such upregulated miRNAs, miR204 and miR10a, which were found to be involved in the regulation of synaptic plasticity and associated cognitive decline in aged mouse hippocampus by repressing their downstream target molecules EphB2 and Camk2B respectively. EphB2 is part of the NMDA signalling pathway which regulates NMDA-receptor-dependent Ca2+ influx and downstream transcription factors involved in LTP formation and synaptic plasticity. I found that aging is accompanied by the upregulation of miR-204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. NR1 subunit of the NMDA receptor (NMDAR), a glutamate- and voltage-activated calcium-permeable ion channel is necessary for inducing forms of synaptic plasticity that contribute to learning and memory. I found that EphB2 is a direct target of miR-204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with miR-204 suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR-204 also decreased the total expression of NR1. miR-204 induces senescence-like phenotype in fully matured neurons as evidenced by increase in p16 positive cells. I also found another miRNA, miR10a is upregulated in aged hippocampus and targets Camk2b, another key molecule which is crucial in several aspects of plasticity and glutamatergic synapses. These mechanisms may contribute to age-associated decline in synaptic plasticity and cognitive function. Thus, age-dependent cognitive impairments could be attributed to increased miR-204 and miR10a expression in hippocampal neurons. I believe that age-regulated miR-204 and miR10a may thus serve as a novel target for nootropic therapy to reverse age-related cognitive decline.