Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4
Open accessAbstract
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 (16p11.2 dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2 dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2 dp/+ 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 16p11.2 dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2 dp/+ 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.
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Restoring Npas4 expression ameliorates social and cognitive deficits, GABAergic synaptic impairment, and neuronal hyperexcitability in 16p11dp/+ mice.
“Restoring the expression of Npas4, a key regulator of GABA synapses 135,136, ameliorates the social and cognitive deficits, as well as GABAergic synaptic impairment and neuronal hyperexcitability in 16p11dp/+ mice 134.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [134]
16p11.2 duplication mouse model exhibits deficient GABAergic synaptic transmission and elevated excitability in PFC pyramidal neurons.
“On the other hand, a 16p11.2 duplication mouse model, 16p11dp/+, exhibits deficient GABAergic synaptic transmission and elevated excitability in PFC pyramidal neurons 134.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [134]
Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801-induced hyperlocomotion, were not observed in 16p11.2dp/+ mice, despite a report on female-specific PPI deficits.
“Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801-induced hyperlocomotion, were not observed in 16p11.2dp/+ mice [72], despite a report on female-specific PPI deficits [73].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
16p11.2dp/+ mice exhibit hypolocomotion, in direct contrast to 16p11.2+/− animals.
“16p11.2dp/+ mice also exhibit hypolocomotion [5, 72, 73], in direct contrast to 16p11.2+/− animals.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
16p11.2dp/+ mice (Mills) exhibit social and cognitive deficits along with increased repetitive self-grooming, with the absence of motor coordination deficits.
“The 16p11.2dp/+ mice (Mills) exhibit social and cognitive deficits [72, 73] along with increased repetitive self-grooming [5, 72], with the absence of motor coordination deficits [72].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
A separate RNA-seq experiment in mPFC of 16p11.2dp/+ mice (Mills) identifies 388 DEGs (277 downregulated, 111 upregulated), confirming broad transcriptional disruption extending far beyond the genes located within the 16p11.2 region.
“A separate RNA-seq experiment in mPFC of 16p11.2dp/+ mice (Mills) identifies 388 DEGs (277 downregulated, 111 upregulated), confirming broad transcriptional disruption extending far beyond the genes located within the 16p11.2 region [72].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
Restoring mPFC GABAergic synaptic activity is sufficient to reverse the social and cognitive deficits in 16p11.2dp/+ mice, implicating prefrontal cortical synaptic dysfunction in 16p11.2 duplication pathology.
“Restoring mPFC GABAergic synaptic activity is sufficient to reverse the social and cognitive deficits [72], implicating prefrontal cortical synaptic dysfunction in 16p11.2 duplication pathology.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
16p11.2dp/+ mice (Mills) display GABAergic synaptic deficits in mPFC pyramidal neurons and increased action potential firing rates.
“The 16p11.2dp/+ mice (Mills) display GABAergic synaptic deficits in mPFC pyramidal neurons and increased action potential firing rates [72].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
Restoring Npas4 expression reverses GABAergic deficits and improves social and cognitive deficits in 16p11.2 duplication mice, but does not affect repetitive grooming.
“a recent study from our group [72] revealed that restoring expression of Npas4, a key regulator of GABA synapses [104, 105] reverses GABAergic deficits and ameliorates social and cognitive deficits in these mice, but not repetitive grooming behavior.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [72]
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References 73 · Cited by 58
- Authors
- Rein, B., Tan, T., Yang, F., Wang, W., Williams, J., Zhang, F., Mills, A., & Yan, Z.
- Affiliations
- University at Buffalo, State University of New York (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Yan, Zhen
- Venue
- Molecular Psychiatry
- Published
- 2020-02-25
- Volume
- 26
- Issue
- 6
- Pages
- 1967-1979
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC7483162
- OpenAlex
- W3006986123
- Cited by
- 58
- References
- 73
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 14 · 2023: 12 · 2022: 7 · 2021: 8 · 2020: 4 · 2014: 1
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- Nancy Lurie Marks Family Foundation
- U.S. Department of Health & Human Services | National Institutes of Health (MH112237, MH108842)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- 16p11.2 duplication, Npas4, GABAergic neurotransmission, neuronal excitability, prefrontal cortex, autism spectrum disorder, intellectual disability, social dysfunction, cognitive impairment, copy number variation, mouse model, transcriptional dysregulation, therapeutic target
- MeSH terms
- Autism Spectrum Disorder, Animals, Chromosome Deletion, Chromosomes, Human, Pair 16, gamma-Aminobutyric Acid, Humans, Synapses, Mice, Basic Helix-Loop-Helix Proteins, DNA Copy Number Variations
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