Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency

Megha Subramanian; William T Mills 4th; Manish D Paranjpe; Uche S Onuchukwu; Manasi Inamdar; Amanda R Maytin; Xinbei Li; Joel L Pomerantz; Mollie K Meffert

doi:10.1016/j.isci.2023.108676

Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency

iScience. 2023 Dec 12;27(1):108676. doi: 10.1016/j.isci.2023.108676. eCollection 2024 Jan 19.

Authors

Affiliations

¹ Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
⁴ Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

Abnormal neuronal and synapse growth is a core pathology resulting from deficiency of the Fragile X mental retardation protein (FMRP), but molecular links underlying the excessive synthesis of key synaptic proteins remain incompletely defined. We find that basal brain levels of the growth suppressor let-7 microRNA (miRNA) family are selectively lowered in FMRP-deficient mice and activity-dependent let-7 downregulation is abrogated. Primary let-7 miRNA transcripts are not altered in FMRP-deficiency and posttranscriptional misregulation occurs downstream of MAPK pathway induction and elevation of Lin28a, a let-7 biogenesis inhibitor. Neonatal restoration of brain let-7 miRNAs corrects hallmarks of FMRP-deficiency, including dendritic spine overgrowth and social and cognitive behavioral deficits, in adult mice. Blockade of MAPK hyperactivation normalizes let-7 miRNA levels in both brain and peripheral blood plasma from Fmr1 KO mice. These results implicate dysregulated let-7 miRNA biogenesis in the pathogenesis of FMRP-deficiency, and highlight let-7 miRNA-based strategies for future biomarker and therapeutic development.

Keywords: Behavioral neuroscience; Molecular neuroscience.

Abstract

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