The Invisible Helmsmen: How Circular RNAs Steer Our Brain's Function

Hidden within the brain's intricate wiring lies a cryptic RNA universe—circular RNAs—whose functions remained elusive for decades.

Navigation

Introduction: The RNA Universe Beyond DNA

While DNA has long been the star of molecular biology, its cousin RNA is the unsung maestro of cellular complexity. Hidden within the brain's intricate wiring lies a cryptic RNA universe—circular RNAs (circRNAs)—whose functions remained elusive for decades. Recent breakthroughs reveal these molecules as master regulators of brain health, with profound implications for neuropsychiatric disorders. When scientists deleted just one circRNA gene in mice, the animals lost a fundamental brain filter—the ability to ignore irrelevant stimuli 1 4 6 . This is the story of how circular RNAs emerged from obscurity to revolutionize neuroscience.

Key Discovery

Deletion of a single circRNA gene impaired the brain's ability to filter irrelevant stimuli, similar to deficits seen in schizophrenia patients.

Significance

circRNAs represent a new layer of gene regulation in the brain, with potential applications in neuropsychiatric disorders.

What Are Circular RNAs?

Unlike linear RNAs, circRNAs form covalently closed loops resistant to degradation. This "ring" structure grants extraordinary stability, allowing them to persist for days in neurons—ideal for maintaining long-term brain functions 4 6 . Of the thousands identified, Cdr1as stands out:

  • Location: Abundant in excitatory neurons (not glia) across human and mouse brains 3 5
  • Binding Partners: Hosts >70 sites for miR-7 and miR-671, two microRNAs regulating synaptic genes 1 6
  • Evolutionary Role: Highly conserved from worms to humans, hinting at critical biological functions 4 6
Circular RNA structure

Artistic representation of circular RNA structure (Credit: Science Photo Library)

Key Insight: circRNAs act as molecular "sponges" or "boats," protecting miRNAs from degradation and ferrying them to synapses 4 6 .

The Landmark Experiment: Deleting Cdr1as

In 2017, Rajewsky's team used CRISPR/Cas9 to knockout the Cdr1as locus in mice, creating the first circRNA loss-of-function model 1 4 7 .

Methodology
  1. Gene Editing: CRISPR excised the Cdr1as locus in mouse embryos
  2. miRNA Profiling: RNA sequencing of 4 brain regions (cortex, hippocampus, etc.)
  3. Electrophysiology: Measured synaptic vesicle release in single neurons
  4. Behavioral Tests: Assessed sensorimotor gating via "prepulse inhibition" (PPI) 1 4 6

Results

Table 1: Behavioral and Synaptic Changes in Cdr1as-KO Mice
Parameter Wild-Type Mice Cdr1as-KO Mice Significance
Prepulse Inhibition Normal Impaired P<0.001
Social Behavior Normal Normal N.S.
Spontaneous Vesicle Release Baseline 2x Increase P<0.01
Response to Sequential Stimuli Normal Depressed P<0.05
Table 2: Molecular Changes in Brain Tissue
Molecule Change in Cdr1as-KO Function Downstream Effect
miR-7 ↓ 50–60% Represses Fos (early gene) ↑ Fos expression
miR-671 ↑ 40–50% Targets Cdr1as for degradation CircRNA destabilization
Synaptic Proteins Altered Regulate neurotransmission Dysfunctional signal filtering

Analysis: Cdr1as loss specifically dysregulated miR-7/miR-671, destabilizing synaptic gene networks. The PPI deficit mirrored schizophrenia patients 1 4 5 .

Why Sensorimotor Gating Matters

Imagine a library where a dropped book triggers panic, but the same noise near a construction site seems unthreatening. This filtering—prepulse inhibition—relies on brain circuits to suppress irrelevant stimuli. Cdr1as-KO mice lost this ability, linking circRNAs to neuropsychiatric disorders 4 6 :

Mechanism

Unchecked miR-7 suppression spiked Fos levels, over-activating neurons.

Broader Impact

circRNAs are enriched in synapses, suggesting roles in "tuning" neural circuits 1 6 .

Neural circuit filtering

Illustration of neural circuits involved in sensorimotor gating (Credit: Science Photo Library)

The Scientist's Toolkit: Key Research Reagents

Table 3: Essential Tools for circRNA Research
Reagent/Method Function Example Use
CRISPR/Cas9 Gene knockout Excising Cdr1as locus in mice
RNase R Treatment Degrades linear RNAs; enriches circRNAs Validating circular transcripts
miRNA Antagomirs Inhibits specific miRNAs Testing miR-7/miR-671 roles
Single-Cell RNA-seq Cell-type-specific profiling Detecting circRNAs in dopamine neurons
CircExplorer2 Bioinformatics for circRNA detection Identifying back-spliced reads
CRISPR/Cas9

Precision gene editing tool used to knockout circRNA loci in model organisms.

RNase R

Enzyme that degrades linear RNAs while leaving circRNAs intact for isolation.

CircExplorer2

Bioinformatics pipeline for identifying circRNAs from RNA-seq data.

Human Implications: circRNAs in Disease

Recent human brain studies reveal circRNAs are cell-type-specific and disease-linked:

  • Dopamine neurons (vulnerable in Parkinson's) produce circDNAJC6, dysregulated in early disease
  • Autism-risk genes generate circRNAs in pyramidal neurons; cancer genes in non-neuronal cells

The Future: circRNAs could be biomarkers or therapeutic sponges to "soak up" dysregulated miRNAs.

circRNA in disease

Potential therapeutic applications of circRNAs (Credit: Science Photo Library)

Conclusion: Sailing the circRNA Seas

The deletion of a single circRNA gene exposed a hidden layer of brain regulation. Cdr1as isn't just a molecular oddity—it's a helmsman guiding synaptic function and cognitive filtering. As Rajewsky proclaimed, "We've uncovered a parallel universe of RNAs" 4 6 . With technologies like laser-capture RNA-seq now profiling circRNAs in individual neurons , we edge closer to decoding their roles in health and disease. These circular voyagers, once dismissed as "junk," may soon steer us toward revolutionary neurotherapies.

Final Thought: In the brain's vast ocean, circRNAs are the buoys marking channels of stability—and their loss risks a synaptic storm.

Key Takeaways
  1. circRNAs are stable, circular RNA molecules abundant in neurons
  2. They regulate microRNAs and synaptic function
  3. Cdr1as knockout impairs sensorimotor gating, similar to schizophrenia
  4. circRNAs show cell-type-specific expression patterns in human brain
  5. Potential applications as biomarkers and therapeutics for brain disorders

References