Poster Presentation Australasian RNA Biology and Biotechnology Association 2026 Conference

Dory lncRNA modulates female-specific hippocampal spatial memory (#102)

Saba Altaf 1 2 , Seonghee Jung 3 , Mitchell Cummins 1 , Lachlan Ferguson 1 2 , Rowan Heggen 1 , Anne Poljak 4 , Kelly Clemens 2 5 , Fabien Delerue 3 , Lars Ittner 3 , John Mattick 1 5
  1. School of Biotechnology and Biomolecular Sciences, Faculty of Science, UNSW, Sydney, NSW, Australia
  2. School of Psychology, Faculty of Science, UNSW, Sydney, NSW, Australia
  3. Dementia Research Centre and Macquarie Medical School, , Faculty of Medicine, Health and Human Sciences, Macquarie University, , Sydney, NSW, Australia
  4. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, and Centre for Healthy Brain Ageing, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  5. UNSW RNA Institute, Kensington, NSW, Australia

Long noncoding RNAs (lncRNAs) are increasingly recognised as important regulators of neuronal gene expression and brain function, yet the functions of most remain unknown. Dory (2700046G09Rik/Sgms1os1) is enriched in the hippocampus and is expressed in excitatory and inhibitory hippocampal neurons, as well as immature neurons and neural stem cells in the dentate gyrus. To define its role in vivo, we generated CRISPR-Cas9 knockout mice targeting the constitutive first exon of Dory and used antisense oligonucleotide (ASO)-mediated knockdown in rat dorsal hippocampus to distinguish transcript-dependent effects from possible consequences of genomic disruption.

Dory knockout (Δ/Δ) mice and wild-type littermates were assessed in open field (OF), object location (OLT), and novel object recognition (NOR) tasks, followed by Morris water maze (MWM) testing. Hippocampal RNA sequencing and mass spectrometry were also performed. In parallel, male and female rats received either Dory-targeting or scrambled control ASOs in the dorsal hippocampus, with knockdown confirmed by qPCR, followed by OF, OLT, NOR, and Barnes maze testing.

Female, but not male, Dory Δ/Δ mice showed impaired object location discrimination and delayed acquisition of spatial learning in the MWM. In contrast, OF behaviour and NOR performance were unchanged in both sexes. Molecular profiling revealed strong sex-dependent hippocampal responses to Dory loss, with limited overlap between males and females. Several genes, including Prl, Gh, and Pomc, were regulated in opposite directions between sexes, and female-specific pathways were enriched for cytokine response and hormone secretion. In rats, Dory ASO knockdown reproduced the female-specific OLT deficit, while OF and NOR remained unaffected in both sexes.

Together, these findings show that Dory is required for female-specific hippocampal spatial memory and support a transcript-dependent mechanism rather than an effect caused solely by genomic deletion. More broadly, they add to growing evidence that lncRNAs contribute to sex differences in cognitive function and hippocampal biology.