Defining the molecular impact of 16p11.2 deletion on reward response in striatal dopamine receptor D1-expressing neurons

PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder, Attention Deficit Hyperactivity Disorder, and Intellectual Disability are a challenging set of conditions with large phenotypic overlap and predominantly unknown etiology. There is a lack of effective interventional strategies to target the most impairing aspects of NDDs, owing largely to a lack of knowledge about their underlying cellular and molecular mechanisms. Deletion of one copy of the 16p11.2 region results in a high penetrance of NDDs in humans, and because it can be faithfully modeled in mice, this deletion is a favored model for the neurobiological study of NDDs. Mice lacking one copy of the genomic region orthologous to the human 16p11.2 region (16p DEL) exhibit behavioral phenotypes with relevance to human NDDs including a male-specific deficit in reward learning. This deficit is recapitulated when 16p DEL is induced specifically in dopamine receptor D1-expressing medium spiny neurons (D1+ MSNs) of the striatum, implicating this neuronal population as critical to reward system dysfunction in NDDs. D1+ MSNs are known to play a critical role in signaling reward and learning action-reward associations, but little is known about how the function of these cells is altered in NDDs. Here, we propose to use the 16p DEL model to delineate how D1+ MSNs respond to reward in the context of NDDs. The ability of neurons to respond to experience and store information is known to require carefully regulated gene expression. During this process neuronal signals are transduced to the nucleus where molecular mechanisms facilitate the expression of specific genes whose products in turn alter neuronal function. Disruptions of these molecular mechanisms are strongly associated with the occurrence of NDDs, and multiple pieces of evidence suggest that the regulation of gene expression is disrupted in 16p DEL mice. The experiments outlined in this proposal will use state-of-the-art transgenic animals and analytical techniques to investigate the molecular mechanisms controlling the reward response of D1+ MSNs in the striatum of 16p DEL mice. In Specific Aim 1, we will characterize gene expression changes induced by reward in this neuronal population. In Specific Aim 2, reward-dependent histone post- translational modifications in 16p DEL D1+ MSNs will be characterized. Finally, in Specific Aim 3, we will outline alterations of calcium signaling in these neurons during a touchscreen operant task. This work promises to reveal the molecular mechanisms underlying reward system dysfunction in an NDD model, which will provide critical insight into the reward-related behavioral phenotypes observed throughout the spectrum of NDDs.