Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4
Authors: Zhen Yan
Benjamin Rein
Freddy Zhang
Wei Wang
Alea Mills
Tao Tan
Jamal Williams
Fengwei Yang
Journal: Molecular Psychiatry (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: 16p11.2 gene locus; copy number variations; neuropsychiatric phenotypes; autism spectrum disorder; intellectual disability
Affiliations: Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA., Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY, 11724, USA., Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA. .

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. 

Retracted: No

PubPeer comments:
 There are two problems: 1. In Fig 5A, the Npas4 mRNA did not show significant reduction in 16p11.2dp + mice, which is inconsistent with the conclusion in Fig4. ![file] . 2. In Fig 5K, the self-grooming time did not increase significantly in 16p11.2 dp + mice, which is inconsistent with the conclusion in Fig1. ![file] , 
 Dr. Ju, Thank you for your comment, and for your careful read of our article. Regarding Fig 5B, the lack of significant Npas4 downregulation is due to limited n values for the 16p+GFP group (n = 4). Since Npas4 downregulation had been extensively confirmed in figure 4, fewer mice were allocated to this group. However, the trend toward Npas4 downregulation is still evident (23% reduction relative to WT) within these few animals. Figure 5K shows a significant self-grooming group effect between WT vs 16p mice with either treatment, as PFC Npas4 upregulation did not affect self-grooming in either genotype. The data presented here are consistent with the modest increase in self-grooming reported in Figure 1F. , 
 #2 Yes, you are right. I am confused that it increases or decreases significantly in one figure, but only shows a trend to increase or decrease in another figure, whether it is OK. anyway, Thanks for your reply! ,