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Circular RNAs (circRNAs) are an emerging class of long non-coding RNAs with complex regulatory potential that can impact gene expression and function. However, the vast majority of circRNAs have not been characterized and little is known about their function in the brain despite their abundance in cortical tissue. Recent work has focused on circRNAs as biomarkers for disease and therapeutics due to their increased stability since their biogenesis through backsplicing renders them resistant to RNA degradation. CircRNAs are developmentally regulated and differentially regulated in brain disorders including Alzheimer’s Disease (AD) and schizophrenia (SCZ). While plasticity-related protein-coding genes have been associated with cognitive dysfunction in these disorders, little is known about the potential for circRNAs in regulating synaptic activity and cognition. A recent paper identified circHomer1 as a candidate molecule in AD in its correlation with duration and severity of illness. The Homer1 gene produces multiple proteins involved in synaptic function and has been implicated in psychiatric disorders including SCZ and major depression. We have shown that circHomer1 is reduced in postmortem orbitofrontal cortex (OFC) from patients with SCZ and bipolar disorder (BD) and that reduction of circHomer1 in rodent OFC is sufficient to produce an OFC-dependent behavioral deficit on a touchscreen visual reversal task. Our current work demonstrates circHomer1 is capable of controlling molecular correlates of behavior and electrophysiological signaling in vitro and in vivo. Using long-term in vivo electrophysiological recordings in OFC during reversal learning in mice, we examine changes in excitatory neuronal activity that underlie OFC dysfunction following loss of circHomer1. Our results indicate changes in OFC local field activity during impaired reversal stages that correlate with those seen in human patients with SCZ. This work is the first to demonstrate a psychiatric-related circRNA can modulate synaptic regulatory processes involved in learning and neuronal activity underlying cognitive impairment.


Poster presented at the Brain & Behavioral Health Research Day 2021



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