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. 2024 Apr 3;44(14):e1610232024.
doi: 10.1523/JNEUROSCI.1610-23.2024.

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

Mark A Deehan  1 , Josine M Kothuis  1 , Ellen Sapp  1 , Kathryn Chase  2 , Yuting Ke  1   3 , Connor Seeley  1 , Maria Iuliano  1 , Emily Kim  1 , Lori Kennington  2 , Rachael Miller  2 , Adel Boudi  1 , Kai Shing  1 , Xueyi Li  1 , Edith Pfister  2   4 , Christelle Anaclet  5 , Michael Brodsky  6 , Kimberly Kegel-Gleason  1 , Neil Aronin  2 , Marian DiFiglia  7
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Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction

Mark A Deehan et al. J Neurosci. .

Abstract

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, behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In the cortex, NACC1 long isoform, which harbors the mutation, increased from 3 to 6 months, whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from postnatal day (P) 7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed over 1,000 differentially expressed genes (DEGs). Glial transcripts were downregulated and synaptic genes upregulated. Top gene ontology terms from upregulated DEGs relate to postsynapse 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.

Keywords: EEG; NACC1; autism; seizure; synapse; transcriptomics.

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Conflict of interest statement

K.K.-G. spouse owns <0.1% stock in the following companies: Advanced Microdevices, Aveo Pharmaceuticals, Boston Scientific, Bristol-Myers Squibb, Cisco Systems, Fate Therapeutics, GE Healthcare Life Sciences, Generex Biotechnology, Idera Pharmaceuticals, Nante Health, Neurometrics, NuGenerex, Repligen, Sesen Bio, T2 Biosystems, and Vericel. The other authors declare no competing financial interests.

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