Neuronal activity-dependent gene expression is essential for brain development. Transcriptional and epigenetic effects of neuronal activity have been extensively explored in mice. However, a recent study from Gabriella Boulting and colleagues has shown that more than one hundred autism-associated genes have previously unreported activity-inducible expression in human stem cell-derived neurons¹, suggesting that the neuronal activity-dependent gene program has evolved differently in primates than in rodents. The current project aims to identify the neuronal activity-regulated genes of the primate genome, and the noncoding DNA regulatory elements that control them, in order to reveal evolved primate-specific genetic sequences that contribute to autism risk.

Agitation and aggression are common, difficult-to-manage challenges for many individuals with autism. In the current project, Alexander Li Cohen plans to identify a specific brain network that has a causal relationship with agitation and aggression, and that is consistent across age and clinical cohorts, including individuals with autism. These studies will take advantage of neuroimaging data and behavioral measures of agitation and aggression that have already been collected from diverse clinical cohorts (including a total of 970 adults and 300 children and adolescents). Results from these studies are expected to inform mechanistic studies of how specific genetic alterations lead to increased agitation and aggression in autism, as well as neuromodulation studies to determine if altering brain activity in this network can reduce agitation and aggression, ultimately leading to novel treatment options.

A significant proportion of high-confidence autism risk genes play a role in chromatin regulation, but it remains unclear how mutations in these genes cause autism². In the current proposal, Eirene Markenscoff-Papadimitriou plans to focus on two autism risk genes, ADNP and POGZ, which encode chromatin regulators with similarities in their structures and functions. She hypothesizes that identifying enhancers dysregulated by heterozygous mutations in these genes can point to the neuronal cell types where autism vulnerability arises. To identify such enhancers, epigenetic and transcriptomic profiling will be performed in mouse models of Adnp and Pogz haploinsufficiency. The function of pathogenic missense and truncating variants will also be assessed in human stem-cell derived cortical neurons.

Cognitive flexibility, the ability to rapidly switch our thinking and actions according to context, is a fundamental component of higher cognition. Changes in cognitive flexibility are common in autism, yet little is known about the underlying neural mechanisms. Marino Pagan has developed paradigms that allow rats to perform complex behaviors that require rapid executive control³. In the current project, he plans to leverage these behavioral paradigms to systematically characterize deficits across different domains of cognitive flexibility in genetic rat models of autism (including Fmr1 and Nrxn1 mutants). He then plans to investigate the neural mechanisms underlying cognitive inflexibility in these models. These studies will involve high-throughput electrophysiology and optogenetic experiments in freely moving, behaving animals.

Functional genomic studies have identified disruption of cortical neurons and their associated circuits during mid-fetal development as a possible convergent etiology of autism. The largest structure in the mid-fetal human developing cortex is the subplate zone, a heterogenous layer of neurons associated cortical circuit assembly. Kartik Pattabiraman plans to perform a comparative multi-level characterization of this cortical layer with a focus on its role in circuit formation and autism pathology. Specifically, he plans to identify and study conserved and species-specific characteristics. He also plans to further characterize subplate-enriched genes, including ASD risk genes, and assess the effect of knockdown of select genes on cortical connectivity.

Many autism risk genes play a role in regulating the epigenetic machinery, including chromatin remodelers and writers and readers of DNA methylation. Exposure to potential environmental risk factors for autism can also remodel the epigenome. This suggests that disruption of the epigenetic landscape may be a converging contributor to autism pathogenesis. In the current study, Zhuzhu Zhang plans to characterize cell type- and circuit-specific epigenomic configurations during normal postnatal brain development in mice and investigate how the epigenomic configurations are altered in genetic mouse models of autism. These studies will provide a better understanding of the interplay of changes in the genome and epigenome in neurodevelopmental conditions.