Reversal of synaptic and behavioral deficits in a 16p11.2 duplication mouse model via restoration of the GABA synapse regulator Npas4

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 (16p11.2 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 the 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 the GABAergic synaptic impairment and neuronal hyper-excitability. 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.

16p11.2 Copy Number Variations and Neurodevelopmental Disorders

“…Thus, 16p11.2 +/− mice may represent a suitable preclinical model system for evaluating mechanisms of certain social and cognitive dysfunctions, but several of the deficits associated with 16p11.2 deletions cannot be modeled in these animals. The 16p11.2 dp/+ 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]. Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801induced hyperlocomotion, were not observed in 16p11.2 dp/+ mice [72], despite a report on female-specific PPI deficits [73].…”

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

“…Memories are believed to be encoded by distributed ensembles of neurons functionally coupled through synaptic potentiation, and the Npas4 gene has been identified as an important regulator of this associative synaptic plasticity (Rein et al, 2020). It was recently reported that Npas4 promotes memory discrimination by enhancing the inhibitory drive from local cholecystokinin (CCK)-expressing interneurons within these ensembles.…”

16p11.2 Duplication Syndrome - a Case Report

“…2 The intellectual disability, which is the leading symptom, could be due to an impaired transmission of Gamma aminobutyric acid in the synapses in animal models. 3 Also, there is an increased incidence of epilepsy and schizophrenia. 2 However, there are no specific dysmorphic features for this genetic condition, but microcephaly, micrognathia and hypertelorism have been documented in other patients with this disorder.…”