The Circular RNA Revolution

For decades, molecular biology centered on a simple paradigm: DNA makes RNA makes protein. RNA was considered merely a messenger—a transient, linear molecule carrying genetic blueprints to protein factories. But nestled within our neurons lies an entire universe of non-coding RNAs that defy this dogma. Among the most enigmatic are circular RNAs (circRNAs), closed loops that float like molecular buoys in our cellular seas. Their discovery unveiled a parallel universe of RNA function, with profound implications for understanding the brain—the organ harboring the richest diversity of these mysterious circles ⁶ .

Unraveling the Circular Enigma

What are Circular RNAs?

Unlike classic linear RNAs with distinct ends, circRNAs form through a "back-splicing" process where the 3' and 5' ends covalently bond into a continuous, unbroken loop. Discovered decades ago but dismissed as rare artifacts, advanced sequencing technologies revealed they are abundant, stable, and evolutionarily conserved, especially in the brain. Their circular structure grants them remarkable longevity, persisting for days in the cytoplasm compared to hours for most linear RNAs—a perfect design for sustained regulatory roles ^{3 6} .

The Landmark Experiment: Deleting a Circular RNA

Methodology: Precision Gene Editing

The team employed CRISPR/Cas9 genome editing to excise the entire Cdr1as locus in mice. They then conducted a multi-level analysis:

• Molecular Profiling: Small RNA sequencing across brain regions (cortex, hippocampus, cerebellum, striatum) to track miRNA levels.
• Electrophysiology: Single-cell recordings in hippocampal neurons to measure synaptic vesicle release and response to stimuli.
• Behavioral Tests: Assessing anxiety, memory, social interaction, and sensorimotor gating via "prepulse inhibition" (PPI) tests.

Results: A Molecular and Behavioral Earthquake

Deleting Cdr1as triggered specific, dramatic effects:

Behavioral Impact: Losing the Filter

While anxiety, memory, and movement appeared normal, Cdr1as-KO mice showed severe prepulse inhibition (PPI) deficits. PPI measures the ability to dampen reactions to a startling noise (e.g., a gunshot) if preceded by a weaker cue (e.g., a whisper). Without Cdr1as, mice couldn't "gate" sensory overload—a hallmark of neuropsychiatric disorders like schizophrenia ^{3 6} .

Why This Matters: From Molecular Boats to Brain Disorders

Beyond Sponges: The "Molecular Boat" Hypothesis

The data challenged the simple "sponge" model. Rajewsky proposed a new analogy: Cdr1as as a molecular boat. Instead of just soaking up miR-7, it stabilizes and transports it to synapses, preventing its degradation. Conversely, miR-671—which cleaves Cdr1as—may regulate the circle's turnover. This dynamic ensures precise miR-7 delivery to control genes like Fos, fine-tuning neuronal responses to stimuli ^{3 6} .

The PPI deficits mirror sensorimotor gating impairments in schizophrenia and ADHD. The upregulation of IEGs like Fos suggests circRNAs help maintain neuronal homeostasis. When disrupted, circuits become hyperexcitable, flooding the brain with irrelevant information—much like failing to tune out construction noise while reading in a café ^{4 6} .

The Ripple Effect in Biomedicine

This work ignited the circRNA field, revealing:

Conclusion: Sailing the Circular Seas

The deletion of a single circular RNA locus unveiled a hidden layer of gene regulation critical for brain function. Cdr1as isn't a passive sponge but an active navigator, ensuring miRNAs reach their destinations to calibrate our responses to the world. As we explore this "parallel universe" of circRNAs—over 100,000 predicted in humans—we edge closer to decoding neuropsychiatric disorders and designing RNA-based therapeutics. The humble RNA circle, once overlooked, now stands as a captain of our synaptic seas, proving that in molecular biology, sometimes the most profound secrets come in circular packages ^{3 6} .