Schizophrenia (SCZ) and Bipolar disorder (BD) are heterogeneous psychiatric disorders that together affect more than 3.5% of the US population. Studies using animal, pharmacological models
and post-mortem data, have revealed abnormalities in the dopaminergic and glutamatergic pathways, however, the pathogenesis remains vague. Non-coding RNAs (ncRNAs) have been shown to play a role in regulating gene expression at the transcriptional and post-transcriptional level and having implications on brain development and psychiatric diseases. Circular RNAs are a category of ncRNAs, formed after back-splicing of exons/introns, covalently linked, enriched in the mammalian brain and derived from genes that are implicated in synaptic plasticity. Homer protein homolog 1 is important for brain functions via regulating glutamatergic synapses, affecting spatial learning and memory. Homer 1 polymorphisms are associated with psychiatric disorders and Homer1 KO mice display symptoms reminiscent of schizophrenia. CircHomer1, is a neuronal-enriched circRNA, derived from exons 2 and 5 of the precursor of the Homer1B mRNA isoform and abundantly expressed in adult frontal cortex.
Previous data have indicated that circHomer1 is significantly altered in postmortem brains of SCZ/BD patients and circHomer1 KD is associated with cognitive disturbances. In my research project, I intend to examine the mechanisms that control circHomer1 biogenesis within neurons. I hypothesize that RNA binding proteins that could bind to the circHomer1 splice junction or in the nearby complementary intronic regions, such as EIF4A3 and GW182, could regulate neuronal circHomer1 biogenesis. Lastly, since circHomer1 is significantly altered in postmortem brains and iPSCs of SCZ/BD patients, I hypothesize that pharmacological intervention for psychiatric disorders can change circHomer1 expression profile. Should that be verified, I will test the molecular cascades that underlie its’ response to psychiatric treatment. All in all, I am aiming in elucidating the molecular mechanisms that may underlie psychiatric diseases by studying circHomer1, an activity and experience dependent, psychiatric disease-associated circRNA.
Papageorgiou, Grigorios and Nikolaos Mellios. "Effects of neuronal activation and psychiatric treatment on circHomer1 Biogenesis." (2021). https://digitalrepository.unm.edu/hsc-bbhrd/20