Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• A specific missense mutation in the Nucleus accumbens-associated 1 (NACC1) gene causes severe neurodevelopmental delay.
• Understanding the molecular and physiological consequences of this mutation is crucial for developing therapeutic strategies.

Purpose of the Study:

• To create and characterize the first mouse model of NACC1-associated neurodevelopmental disorder.
• To investigate the phenotypic, cellular, and molecular changes in mice carrying the homologous NACC1 mutation.

Main Methods:

• Engineered a mouse model with the homologous NACC1 mutation (c.892C>T).
• Conducted electroencephalography (EEG), behavioral analysis, Western blotting, and RNA sequencing (RNA-seq) from embryonic to adult stages.
• Examined NACC1 protein isoforms and immunoreactivity in cortical neurons and glial cells.

Main Results:

• Mutant mice exhibited delayed weight gain, epileptiform discharges, seizures, and hindlimb clasping.
• RNA-seq revealed over 1,000 differentially expressed genes, with downregulated glial transcripts and upregulated synaptic genes.
• Increased nuclear NACC1 immunoreactivity was observed in specific neuronal populations, while astrocytic markers were diminished.

Conclusions:

• The NACC1 mouse model accurately recapitulates key features of the human neurodevelopmental disorder.
• This model provides a valuable platform for studying the pathophysiology of NACC1-related disorders, including rare forms of autism.
• The findings highlight potential therapeutic targets related to synaptic function and glial support.