MicroRNA-210 Knockout Alters Dendritic Density and Behavioural Flexibility

Abstract

MicroRNAs exert post-transcriptional control over eukaryotic genomes and are integral for regulating complex functions in neurodevelopment, neuroplasticity and cognitive processing. The microRNA-210 (miR-210) is a highly-conserved, hypoxia-regulated miRNA that has been shown to be dysregulated in Alzheimer's Disease. We have recently also identified a significant enrichment of neurodegenerative diseases among miR-210 targets within the human transcriptome. To further elucidate the role of miR-210 in neuronal function and cognitive behaviour, we utilised conditional miR-210 knockout mice to characterise miR-210 regulation and function in primary hippocampal neurons and measured visual discrimination and reversal learning using rodent touchscreen assays.We found that miR-210 expression was induced by neuronal activation and loss of neuronal miR-210 increased oxidative metabolism and ROS production as well as dendritic density and branching in vitro. We also found that loss of miR-210 in knockout mice increased behavioural flexibility and reduced perseverative responding during reversal learning which required updating of information and feedback. These data support a conserved, activity-dependent role for miR-210 in cognitive function through modulation of neuronal metabolism.

The role of microRNAs in neurobiology and pathophysiology of the hippocampus

“…Moreover, the expression level of miR-210 increases following neural stimulation. In hippocampal neurons, loss of miR-210 increased oxidative phosphorylation and ROS generation in hypoxia situation and increases dendritic arbor spines in the hippocampus (Watts et al, 2021). Moreover, miR-210 knockout in mice displayed deficits in behavioral and learning abilities.…”

“…Moreover, miR-210 knockout in mice displayed deficits in behavioral and learning abilities. These observations suggested a conserved and stimuli-dependent role for miR-210 in neural development and cognition (Watts et al, 2019(Watts et al, , 2021. It has been reported that miR-17-92 cluster induces neurogenesis as well as neuronal differentiation in the dentate gyrus (DG) through down regulation of a cytoskeleton associated protein, Enigma homolog 1 (Enh1) (Pan et al, 2019).…”

“…In this process, cells move from their place of origin to their site of integration (Faini et al, 2021). Although it seems that extensive neuronal migration is specific to embryonic stages and the beginning (Magill et al, 2010;Mendoza-Viveros et al, 2017) miR-124a NeuroD1, Notch,LHX2 Apoptosis, axonal development (Sanuki et al, 2011;Konrad and Song, 2021) miR-134 LIMK1 Synaptic compartments, dendritic spine formation (Katsu et al, 2019) miR379-410 MEF2 Dendritic outgrowth, synaptic formation (Fiore et al, 2009) miR-210 SNAP25 Dendritic arbor spine density (Ren et al, 2018;Watts et al, 2021) miR-9 REST, NR2E1, SIRT1, FOXG1 Dendritic growth, synaptic transmission, neurogenesis (Giusti et al, 2014) MiR-19 RAPGEF2 Cell migration (Han et al, 2016) miR-200 ZEB1 and ZEB2, PRKAR2B Cell proliferation, synaptic formation (Beclin et al, 2016;Weise et al, 2019) miR-153 JAGGED1 and HEY2 Neurogenesis, glycogenesis (Qiao et al, 2020) miR-184 NUMBL Proliferation and differentiation (Liu et al, 2010;Lang and Shi, 2012) miR-125 BMF,LIN28 Neurogenesis, neuronal survival (Cui et al, 2012) miR-29a FSTL1 Neuronal morphology and neurite outgrowth (Ma et al, 2020) MECP2, methyl-CpG binding protein 2; LHX2, LIM homeobox 2; LIMK1, LIM domain kinase 1; MEF2, myocyte enhancing factor 2; SNAP25, synaptosome associated protein 25; FOXG1, forkhead box protein G1; REST, RE1 silencing transcription factor; NR2E, nuclear receptor subfamily 2 group E member 1; SIRT1, silent mating type information regulation 2 homolog 1; RAPGEF2, Rap guanine nucleotide exchange factor 2, ZEB, zinc finger E-box binding homeobox; PRKAR2B, protein kinase cAMP-dependent type II-Beta regulatory subunit; HEY2, Hairy/ enhancer-of-split related with YRPW motif protein 2; NUMBL, NUMB like endocytic adaptor protein; BMF, Bcl2 modifying factor; FSTL1, Follistatin like 1. 2021).…”