Disrupted Choline Clearance and Sustained Acetylcholine Release In Vivo by a Common Choline Transporter Coding...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neuronal high-affinity choline transporter (CHT; SLC5A7) is crucial for acetylcholine (ACh) synthesis and release.
• A common CHT coding variant (Ile89Val) is linked to reduced human attentional control and frontal cortex activation.

Purpose of the Study:

• To investigate the functional consequences of the CHT Val89 variant using a CRISPR/Cas9-generated mouse model.
• To assess CHT-mediated choline transport, ACh release, and attentional performance in Val89 mice.

Main Methods:

• CRISPR/Cas9 gene editing to create Val89 variant mice.
• In vivo assessment of choline transport and ACh release.
• Behavioral testing using a visual disruptor task.
• Structural modeling of the CHT protein.

Main Results:

• Val89 mice exhibited over 80% reduced choline clearance in the cortex and over 50% in the striatum.
• Mutant mice showed deficits in sustained ACh release and impaired cognitive flexibility during an attentional challenge.
• CHT density was unaffected, indicating a selective impact on transporter function.

Conclusions:

• The CHT Val89 variant impairs choline transport and cholinergic signaling, leading to attentional deficits.
• The CHT Val89 mouse model provides a valuable tool for studying heritable cognitive disorders linked to cholinergic dysfunction.
• Findings offer a mechanistic framework for understanding attentional phenotypes associated with the human Val89 variant.