Rescue of Synaptic and Behavioral Deficits in a Genetic Autism Mouse Model

Benjamin Rein

Ben presenting his research at the 2020 annual 3 Minute Thesis competition hosted by UB. .

Ben presenting his research at UB's 2020 3-Minute Thesis competition. 

Graduate Student Project


You may not find it surprising that 1/54 children is diagnosed with autism spectrum disorder. However, with so many children affected, you may find it surprising that there are no existing drug treatments which can improve the social symptoms of autism. My name is Ben Rein; I'm a fourth year Neuroscience PhD student working with SUNY Distinguished Professor Dr. Zhen Yan, studying the role of gene mutations in autism. We know that about 60% of all autism cases are caused by gene mutations, but it is still unclear why or how these mutations lead to autism. In my work with Dr. Yan, I am studying how one of the most common autism-linked gene mutations, the duplication of a genomic region called "16p11.2" (chromosome 16, position 11.2), changes the development of the brain. We found that mice carrying this 16p11.2 duplication displayed social and cognitive deficits, along with impaired synaptic transmission in the prefrontal cortex (PFC), a key brain area involved in social interaction. However, by elevating the expression of a molecule called Npas4 in this brain area, we were able to restore healthy synaptic communication, but more importantly, this significantly improved the sociability and cognitive function of these mice, to the point where they were indistinguishable from healthy mice. This research indicates that targeting Npas4 may represent a new molecular strategy for therapeutic intervention in autism spectrum disorder.


The human 16p11.2 gene locus is a hotspot for copy number variations predisposing to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD) and intellectual disability (ID), though the underlying molecular mechanisms remain poorly understood. We performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social/cognitive deficits reminiscent of ASD/ID phenotypes. We also detected 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 PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in 16p11.2dp/+ PFC ameliorated the social and cognitive deficits and reversed the GABAergic synaptic impairment and neuronal hyper-excitability. These findings suggest that PFC GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent targets for therapeutic intervention in ASD.

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