Small Genetic Variation Impacts Brain Connectivity

A new study from the Institute for Basic Science (IBS) has uncovered a four-amino-acid sequence that affects brain connectivity and function. This microexon, known as mini-exon B, is part of the genetic code for PTPδ, a protein involved in synapse formation. The research sheds light on how subtle variations in gene expression may contribute to neurodevelopmental and psychiatric conditions.

Conducted by the Center for Synaptic Brain Dysfunctions at IBS and led by Director Kim Eunjoon, the work is the first in vivo study to describe the role of mini-exon B in brain signaling. The gene segment was found to be essential for the development of excitatory synapses in specific types of neurons and to affect animal behavior when deleted.

Role of PTPδ in brain connectivity

PTPδ is a synaptic adhesion molecule that supports the alignment of neurons across synapses. This positioning is necessary for the effective transmission of signals between brain cells. The research team focused on alternative splicing, a cellular process in which parts of the genetic sequence are selectively included or excluded to create protein variants. Mini-exon B is one such element introduced by this mechanism.

Using genetically modified mice, the researchers removed mini-exon B from the PTPδ gene. Mice completely lacking this microexon had low survival rates after birth. Those that retained a single modified gene survived into adulthood but showed anxiety-like traits and reduced movement.

Disrupted synaptic balance

Electrophysiological analysis showed changes in synaptic activity among specific neuron types. Granule cells, which process incoming signals, received reduced excitatory input, while interneurons, which regulate overall network activity, received stronger excitatory signals. This imbalance is consistent with excitation–inhibition shifts reported in neurodevelopmental and psychiatric conditions such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).

Mini-exon B enables cell-type specific interactions

Further investigation revealed that PTPδ’s ability to bind with a partner protein, IL1RAP, depends on the presence of mini-exon B. Without it, the molecular complex does not form, disrupting the assembly of excitatory synapses. The interaction is specific to certain cell types, which may explain the differential effects observed in various brain regions.

The research supports emerging evidence that microexons – small alternative splicing elements – can influence protein function in ways that are highly specific to brain circuits and behavioral outcomes.

Broader significance in neuropsychiatric conditions

The study adds to a growing body of work showing that small genetic variations in splicing can have large-scale effects on brain development. Disorders such as ASD and ADHD have previously been linked to disruptions in synapse formation. This research points to one molecular mechanism that may be involved, reinforcing the need to consider alternative splicing in disease models.

While further research is needed to confirm whether similar mechanisms are at work in humans, the findings provide new directions for understanding synaptic imbalance in brain disorders.

Reference: Kim S, Shin JJ, Kang M, et al. Alternatively spliced mini-exon B in PTPδ regulates excitatory synapses through cell-type-specific trans-synaptic PTPδ-IL1RAP interaction. Nat Comm. 2025;16(1):4415. doi: 10.1038/s41467-025-59685-3

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