Rein, B., Tan, T., Yang, F., Wang, W., Williams, J., Zhang, F., Mills, A., Yan, Z.
(February 2020)
Reversal of Synaptic and Behavioral Deficits in a 16p11.2 Duplication Mouse Model via Restoration of the GABA Synapse Regulator Npas4.
Mol Psychiatry.
ISSN 1359-4184
Abstract
The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.
| Item Type: |
Paper
|
| Subjects: |
bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > mental disorders
diseases & disorders > mental disorders > personality disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > mental disorders > schizophrenia
organism description > animal
diseases & disorders > mental disorders > personality disorders > autism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons > GABAergic interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons > GABAergic interneurons
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons > GABAergic interneurons
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organism description > animal > mammal > rodent
organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions
organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > synapse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Mills lab |
| Depositing User: |
Adrian Gomez
|
| Date: |
25 February 2020 |
| Date Deposited: |
06 Apr 2020 14:18 |
| Last Modified: |
01 Feb 2024 16:59 |
| PMCID: |
PMC7483162 |
| Related URLs: |
|
| URI: |
https://repository.cshl.edu/id/eprint/39224 |
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