A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

Hafez, Alexander; Zimmerman, Amber; Papageorgiou, Grigorios; Chandrasekaran, Jayapriya; Amoah, Stephen; Lin, Rixing; Lozano, Evelyn; Pierotti, Caroline; Dell’Orco, Michela; Hartley, Brigham J.; Alural, Begüm; Lalonde, Jasmin; Esposito, John M.; Berretta, Sabina; Squassina, Alessio; Chillotti, Caterina; Voloudakis, Georgios; Shao, Zhiping; Fullard, John F.; Brennand, Kristen J.; Turecki, Gustavo; Roussos, Panos; Perlis, Roy H.; Haggarty, Stephen J.; Perrone‐Bizzozero, Nora I.; Brigman, Jonathan L.; Mellios, Nikolaos

doi:10.1016/j.celrep.2021.110282

Cited by 28 publications

(72 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding neuronal ring properties at baseline, we found that, although baseline (pre-choice) ring rate is dynamic across reversal learning, the profound reduction in baseline ring rate of circHomer1 KD neurons during chance reversal may be detrimental to learning at this stage and represent an altered homeostatic response to network activity [80]. Homer1 isoforms are well-known for their activity-regulated homeostatic reorganization of the postsynaptic neuron [18] , and this work reinforces the idea that circHomer1 may be in uencing linear Homer1 isoform localization at the synapse [31] in response to increased network demands required for e cient learning.…”

Section: Low Expression Of Circhomer1 In Rodent Ofc Induces Psychiatr...supporting

confidence: 73%

“…While there is a degree of overlap in circHomer1 expression in patients and controls [31,32] as well as in our animal model [32] (and current work), its expression may be more predictive of a particular behavioral phenotype such as behavioral in exibility that spans multiple disorders rather than any speci c disease as a whole. We present ndings that suggest circHomer1 in uences neuronal signaling and coordination within the OFC during speci c windows critical for e cient learning.…”

Section: Circhomer1 Maintains Cellular Ring Potentialmentioning

confidence: 69%

“…KD of circHomer1 was previously predicted to result in reduced synaptic activity through gene expression analysis [32]; however, the molecular mechanism by which this occurs is unclear. Homer1 is homeostatically regulated through alternative splicing [23], and knockdown of the activity-dependent isoform, circHomer1, has been shown to increase both constitutive, Homer1b, and activity-dependent, Homer1a, mRNA localization into the synapse [31,32]. An increase in synaptic Homer1b has been associated with neuronal hyperexcitability in disease [74], while increased synaptic Homer1a is often associated with a homeostatic renormalization [15,23,30] and reduced neuronal excitability [75,76].…”

Section: Low Expression Of Circhomer1 In Rodent Ofc Induces Psychiatr...mentioning

confidence: 99%

“…Future work will be needed to determine associations with circHomer1 expression and human cognitive exibility, but our results provide a promising rationale for this work. Because circHomer1 expression is associated with multiple neurological and psychiatric disorders such as Alzheimer's disease [38][39][40], Parkinson's disease [42], mesial temporal lobe epilepsy [41] and SCZ and BD [31,32], there is likely a convergent mechanism by which synaptic dysfunction results in the ultimate reduction of circHomer1 that promotes brain region-speci c phenotypes.…”

Section: Circhomer1 Maintains Cellular Ring Potentialmentioning

confidence: 99%

See 3 more Smart Citations

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

Zimmerman¹,

Weick²,

Papageorgiou³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Low Expression Of Circhomer1 In Rodent Ofc Induces Psychiatr...supporting

confidence: 73%

Section: Circhomer1 Maintains Cellular Ring Potentialmentioning

confidence: 69%

Section: Low Expression Of Circhomer1 In Rodent Ofc Induces Psychiatr...mentioning

confidence: 99%

Section: Circhomer1 Maintains Cellular Ring Potentialmentioning

confidence: 99%

See 2 more Smart Citations

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

Zimmerman¹,

Weick²,

Papageorgiou³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…RNA interaction has recently gained popularity as a research topic. Currently, circRNA have also been shown to possesses the ability to interact with speci c mRNA and affected them stability, which in turn regulates tumorigenesis and development [33,34]. However, the important role of circRNA that bind to speci c mRNA in HCC is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

A novel circulating RNA circELMOD3 functions as a tumor suppressor in hepatocellular carcinoma through TRIM13/P53 signal axis

Lai

Zeng

Liu

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Circular RNAs (circRNAs) have been identified as key regulatory factors in tumor development based on accumulating studies. However, the underlying molecular mechanisms of the circulating circRNAs in hepatocellular carcinoma (HCC) haven't t been fully elucidated. Methods Five pairs of HCC and adjacent normal tissues were processed using RNA-sequencing to determine the differential expressed circRNAs. The expression levels of genes and proteins were detected by qPCR and Western blotting, respectively. CCK-8, EdU, Flow cytometry, wound healing assay, Transwell assays, and xenograft mouse model were performed to investigate the biological function of circELMOD3 both in vitro and in vivo. Fluorescence in situ hybridization (FISH), RNA antisense purification (RAP) and dual luciferase reporter assay were carried out to verify the interaction between circELMOD3, miR-6864-5P and TRIM13. Results CircELMOD3 was downregulated in plasma and tissues from HCC patients and was related to their clinicopathological characteristics. Significantly, plasma circELMOD3 was shown to be a highly sensitive and non-invasive biomarker to distinguish HCC from healthy controls (AUC = 0.908). Functionally, circELMOD3 prevented HCC cells from proliferating and caused them to undergo apoptosis both in vitro and in vivo. Mechanistically, circELMOD3 increased the expression of TRIM13 by acting as a sponge for miR-6864-5P. In addition, overexpression of circELMOD3 lead to enhanced stability and higher expression level of TRIM13 mRNA, to which it directly binds, and in turn activated the P53 signaling pathway. Conclusion CircELMOD3 plays a tumor suppressor role in HCC via TRIM13/P53 signaling axis, which can serve as a potential target for early diagnosis and treatment of HCC patient.

show abstract

Circular RNAs: Characterization, cellular roles, and applications

Liu

Chen

2022

Cell

528

301

View full text Add to dashboard Cite

A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

Cited by 28 publications

References 74 publications

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

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

A novel circulating RNA circELMOD3 functions as a tumor suppressor in hepatocellular carcinoma through TRIM13/P53 signal axis

Circular RNAs: Characterization, cellular roles, and applications

Contact Info

Product

Resources

About