Tiny Genetic Code Disruption Alters Brain Wiring and Behavior

Summary: A small genetic sequence called mini-exon B plays a surprisingly crucial role in how neurons form synaptic connections, according to new research. Scientists found that deleting this four–amino acid segment from a synapse-building protein, PTPδ, disrupted neural activity and led to anxiety-like behaviors in mice.

The mini-exon enables PTPδ to bind with another protein, IL1RAP, forming a complex critical for excitatory synapse development. This discovery helps explain how subtle changes in genetic splicing may contribute to neurodevelopmental disorders like autism, ADHD, and OCD.

Key Facts:

• Mini-Exon B Function: A 4–amino acid segment in PTPδ enables essential synaptic protein interactions.
• Neural Imbalance: Removing mini-exon B caused reduced survival, synaptic dysfunction, and anxiety-like behaviors in mice.
• Disease Link: The disrupted signaling pathway mirrors patterns seen in autism, ADHD, and OCD.

Source: Institute for Basic Science

Researchers at the Institute for Basic Science (IBS) have identified a remarkably small but critical piece of genetic code that helps determine how brain cells connect, communicate, and function.

The discovery not only deepens our understanding of how the brain’s wiring is built but may also explain the origins of several neurological and psychiatric conditions.

The study, conducted by the Center for Synaptic Brain Dysfunctions at IBS and led by Director KIM Eunjoon (Distinguished Professor at KAIST), focuses on a protein called PTPδ—a key molecule that helps neurons form synapses, the connections that allow brain cells to pass signals.

While PTPδ has already been linked to disorders such as autism spectrum disorder (ASD), ADHD, OCD, and restless leg syndrome, the researchers have now zoomed in on a previously unstudied detail: a tiny segment known as mini-exon B.

This mini-exon is created through a process called alternative splicing, in which cells include or exclude specific snippets of genetic material to slightly alter the structure—and function—of a protein. Mini-exon B is just four amino acids long, yet the team found it plays a surprisingly powerful role in brain development and behavior.

A Closer Look at the Brain’s Synaptic “Glue”

he brain’s ability to think, feel, and move depends on a delicate balance of electrical and chemical signals. These signals travel across synapses, where one neuron passes a message to the next. Proteins like PTPδ help these synapses form properly by acting like molecular Velcro—linking neurons together with precise alignment.

In their study, the researchers genetically engineered mice to delete mini-exon B from the PTPδ gene. The results were dramatic: Mice missing mini-exon B entirely had a survival rate of less than 30% after birth, highlighting its essential role in early brain development and viability.

On the other hand, mice with one copy of the gene altered survived into adulthood but displayed clear behavioral changes, including anxiety-like behavior and reduced movement.

The brain recordings in these mice also showed a misbalance in synaptic activity. Granule cells—neurons responsible for processing information—received weaker excitatory input, while interneurons, which help keep brain activity in check, received stronger excitatory signals. This excitation-inhibition imbalance is a hallmark feature of various neurodevelopmental and psychiatric disorders.

Molecular Clues: A Lock-and-Key Partnership

To uncover how this tiny segment affects brain signaling, the researchers examined the proteins interacting with PTPδ. They discovered that PTPδ forms a molecular complex with another protein called IL1RAP—but only when mini-exon B is present. Without this mini-exon, PTPδ loses its ability to engage IL1RAP, disrupting a critical pathway for forming excitatory synapses.

This interaction turned out to be cell-type specific, meaning it behaves differently depending on which neurons are involved. This level of specificity explains why the deletion of mini-exon B affects some parts of the brain more than others.

Director KIM Eunjoon remarked, “This study illustrates how even the tiniest genetic element can tip the balance of neural circuits. It’s a compelling reminder that errors in alternative splicing could have profound consequences in brain disorders.”

Implications for Human Brain Disorders

This is the first in vivo study to demonstrate the function of PTPδ’s mini-exon B. The findings are especially relevant given the growing evidence that disruptions in microexon splicing may underlie several neuropsychiatric conditions.

Conditions like autism and ADHD have been increasingly linked to impaired synaptic development, and this study helps explain one mechanism by which that might happen. It also highlights the need to study not just genes themselves but the tiny variations in how they’re assembled by the cell’s machinery.

Looking ahead, these insights could inform the development of therapies that target splicing regulation or help restore normal synaptic balance in affected individuals.

The research was conducted in collaboration with KAIST, KBSI, KISTI, Kyungpook National University, and Yonsei University.

About this genetics and neuroscience research news

Author: Eunjoon Kim
Source: Institute for Basic Science
Contact: Eunjoon Kim – Institute for Basic Science
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Alternatively spliced mini-exon B in PTPδ regulates excitatory synapses through cell-type-specific trans-synaptic PTPδ-IL1RAP interaction” by Seoyeong Kim et al. Nature Communications

Abstract

Alternatively spliced mini-exon B in PTPδ regulates excitatory synapses through cell-type-specific trans-synaptic PTPδ-IL1RAP interaction

PTPδ, encoded by PTPRD, is implicated in various neurological, psychiatric, and neurodevelopmental disorders, but the underlying mechanisms remain unclear.

PTPδ trans-synaptically interacts with multiple postsynaptic adhesion molecules, which involves its extracellular alternatively spliced mini-exons, meA and meB. While PTPδ-meA functions have been studied in vivo, PTPδ-meB has not been studied.

Here, we report that, unlike homozygous PTPδ-meA-mutant mice, homozygous PTPδ-meB-mutant (Ptprd-meB^–/–) mice show markedly reduced early postnatal survival.

Heterozygous Ptprd-meB^+/– male mice show behavioral abnormalities and decreased excitatory synaptic density and transmission in dentate gyrus granule cells (DG-GCs). Proteomic analyses identify decreased postsynaptic density levels of IL1RAP, a known trans-synaptic partner of meB-containing PTPδ.

Accordingly, IL1RAP-mutant mice show decreased excitatory synaptic transmission in DG-GCs. Ptprd-meB^+/– DG interneurons with minimal IL1RAP expression show increased excitatory synaptic density and transmission.

Therefore, PTPδ-meB is important for survival, synaptic, and behavioral phenotypes and regulates excitatory synapses in cell-type-specific and IL1RAP-dependent manners.