Project Summary/Abstract Neural mechanisms of ASH1L in autism spectrum disorder Social deficits are the core phenotypes of children with autism spectrum disorder (ASD). One important but unresolved question is the neural mechanisms driving social deficits. Human genetic studies have identified histone methyltransferase ASH1L as a high-risk gene for ASD. We have found that Ash1l haploinsufficiency mice displayed social deficits, which recapitulated the core symptoms in ASD patients. The goal of this proposal is to determine the neural circuits driving ASH1L haploinsufficiency-associated social deficits. Pioneering studies have shown that neuromodulator acetylcholine plays an essential role in attention and cognition. Cholinergic neurons in the basal forebrain (BF) are the major acetylcholine output to the downstream regions such as prefrontal cortex (PFC), a key brain region involved in social behavior and impaired in children with ASD. However, it is unknown which if any of cholinergic projections play a causal role in ASH1L haploinsufficiency- associated social deficits. We hypothesize that impaired cholinergic circuits from BF drive social deficits in Ash1l haploinsufficiency mice. To test this, we will use combination of cutting-edge techniques to address two Specific Aims: (1) To determine diminished cholinergic neuronal activity in the BF driving social deficits in Ash1l haploinsufficiency mice. Brain slices recording, in vivo multichannel recordings and chemogenetic technology will be used to examine the cholinergic neuronal activity in the BF at cellular and in vivo levels. (2) To determine cholinergic neural circuits from BF mediating social deficits in Ash1l haploinsufficiency mice. By combining optogenetic and chemogenetic tools to manipulate cholinergic neuronal activity, we will examine specific cholinergic transmission from BF to PFC in Ash1l haploinsufficiency mice at circuit level. This proposal will address important neural underpinnings of ASD-associated social deficits. The results from this project will provide a novel cholinergic circuit driving ASH1L haploinsufficiency-related social deficits, and shed new light on the development of therapeutic interventions for ASD children by activation of cholinergic system.

Project Narrative ASD affects 1 in 44 children with a ratio of about 1 female for every 4 males in the US and the rates are keeping on increasing. This proposal is to discover novel cholinergic circuits driving ASH1L-associated social deficits, a high-risk gene for ASD. Results gained from this proposal will provide currently unavailable insights into cholinergic neural circuits in ASD-related social deficits and mechanisms-based support for testing therapeutic potential of current FDA-approved cholinergic medications in ASD patients.