Regulation of neuronal circHomer1 biogenesis by PKA/CREB/ERK-mediated pathways and effects of glutamate and dopamine receptor blockade.

There are currently only very few efficacious drug treatments for SCZ and BD, none of which can significantly ameliorate cognitive symptoms. Thus, further research is needed in elucidating molecular pathways linked to cognitive function and antipsychotic treatment. Circular RNAs (circRNAs) are stable brain-enriched non-coding RNAs, derived from the covalent back-splicing of precursor mRNA molecules. is a neuronal-enriched, activity-dependent circRNA, derived from the precursor of the long mRNA isoform, which is significantly downregulated in the prefrontal cortex of subjects with psychosis and is able to regulate cognitive function. Even though its relevance to psychiatric disorders and its role in brain function and synaptic plasticity have been well established, little is known about the molecular mechanisms that underlie biogenesis in response to neuronal activity and psychiatric drug treatment. Here we suggest that the RNA-binding protein (RBP) FUS positively regulates neuronal expression. Furthermore, we show that the MEK/ERK and PKA/CREB pathways positively regulate neuronal expression, as well as promote the transcription of and , another RBP previously shown to activate biogenesis. We then demonstrate via both and studies that NMDA and mGluR5 receptors are upstream modulators of expression. Lastly, we report that D2R antagonism increases expression, whereas 5HT2AR blockade reduces levels in multiple brain regions. Taken together, this study allows us to gain novel insights into the molecular circuits that underlie the biogenesis of a psychiatric disease-associated circRNA.