Nacc1 mutation in mice models rare neurodevelopmental disorder with underlying synaptic dysfunction.

A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay (Schoch et al 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram (EEG), behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In cortex, NACC1 long isoform, which harbors the mutation, increased from 3-6 months whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from P7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein (GFAP) staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed altered expression of over 1000 genes (DEGs). Glial transcripts were downregulated, and synaptic genes upregulated. Top GO terms from upregulated DEGs relate to post synapse and ion channel function while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.Significance statement A missense mutation causing an arginine to tryptophan (R>W) mutation at amino acid 298 in the Nucleus accumbens-associated protein 1 (NACC1) causes profound neurodevelopmental arrest in humans. NACC1 is a transcription repressor but how the R298W mutation causes disease in brain is unclear. We engineered the first mouse model with this mutation and found delayed weight gain, deficits in the open field signaling anxiety, motor dysfunction, and cortical EEG disturbance akin to absence seizures. Females displayed more deficits than males. NACC1 protein increased in neurons in multiple brain regions including cortex and RNA-sequencing and protein studies in postnatal mice revealed dysregulated synaptic pathways. This mouse model recapitulates patient symptoms and provides robust cellular and molecular benchmarks for therapeutic testing.