Knockdown of circHomer1 in the orbitofrontal cortex results in differential encoding of salient stimuli

Abstract

BackgroundCircHomer1 is an activity-dependent circular RNA (circRNA) isoform produced from back-splicing of the Homer1 transcript. Homer1 isoforms are well-known regulators of homeostatic synaptic plasticity through post-synaptic density scaffold regulation. Homer1 polymorphisms have been associated with psychiatric diseases including schizophrenia (SCZ) and bipolar disorder (BD). Postmortem tissue from patients with SCZ and BD showed reduced circHomer1 levels within the orbitofrontal cortex (OFC), a region associated with behavioral flexibility. While dysregulation of circHomer1 expression has recently been identified across multiple psychiatric and neurodegenerative disorders and is associated with impaired behavioral flexibility in mice, it is unknown whether circHomer1 can induce electrophysiological signatures relevant to cognitive dysfunction in these disorders.MethodsCircHomer1 was knocked down in bilateral orbitofrontal cortex of C57BL/6J male mice and in vivo microarray recordings were captured throughout a touchscreen reversal learning task to identify electrophysiological changes associated with reduction of circHomer1. Following task completion, qRT-PCR was used to quantify transcriptional changes following circHomer1 knockdown.ResultsKnockdown of circHomer1 within the OFC induced robust changes in multiunit firing rate and local field potential coordination and power to salient stimuli during reversal learning. Further, these electrophysiological changes were associated with transcriptional downregulation of glutamatergic signaling effectors and behavioral alterations leading to impaired cognitive flexibility.ConclusionsCircHomer1 is a stable biomolecule, whose knockdown in rodent OFC produces lasting electrophysiological and transcriptional changes important for efficient reversal learning. This is, to our knowledge, the first demonstration of a psychiatric-associated circRNA contributing to electrophysiological, transcriptional, and behavioral alterations relevant to psychiatric phenotypes.