Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression

Orna Issler, Yentl Y. van der Zee, Aarthi Ramakrishnan, Junshi Wang, Chunfeng Tan, Yong Hwee E. Loh, Immanuel Purushothaman, Deena M. Walker, Zachary S. Lorsch, Peter J. Hamilton, Catherine J. Peña, Erin Flaherty, Brigham J. Hartley, Angélica Torres-Berrío, Eric M. Parise, Hope Kronman, Julia E. Duffy, Molly S. Estill, Erin S. Calipari, Benoit LabontéRachael L. Neve, Carol A. Tamminga, Kristen J. Brennand, Yan Dong, Li Shen, Eric J. Nestler

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression. Issler et al. demonstrate that long non-coding RNAs are robustly regulated in the brains of postmortem depressed humans in a brain site- and sex-specific manner. LINC00473 is highlighted as key regulator of mood in females only, where it acts in prefrontal cortex by regulating gene expression, neurophysiology, and behavior.

Original languageEnglish (US)
Pages (from-to)912-926.e5
Issue number6
StatePublished - Jun 17 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience


  • CREB
  • depression
  • lncRNA
  • sex-differences


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