In this project, Bence Ölveczky aims to garner insight into the neural circuit-level changes associated with autism and how these lead to motor-related manifestations of the condition. To this end, the project will combine long-term continuous neural recordings in the striatum with quantitative measurements of behavior in freely behaving rats.

The syndromic autism gene, MEF2C, plays an essential role in both neuronal and neuroimmune aspects of brain development and function. In the current project, Christopher Cowan, Hainan Lang and Bärbel Rohrer aim to explore the impact of neuroimmune Mef2c hypofunction on the development and function of mouse auditory and visual sensory systems.

Nael Nadif Kasri will assess differences in neuronal network activity and transcriptional profiles in neural cells derived from induced pluripotent stem cells from individuals with syndromic forms of ASD, building a phenotypic map based on network activity and cellular profiles. These phenotypic maps will aid in the dissection of the underlying cellular and molecular mechanisms involved in distinct forms of ASD.

Each individual with ASD is unique, and understanding this variability is essential for both biomarker and treatment development. Joshua Hartshorne and Stefano Anzellotti plan to use Bayesian nonparametric techniques to analyze functional brain imaging data from individuals with ASD and related neurodevelopmental disorders. The goal of the study is to identify an optimal model that captures variability and clusters the data based on either subtypes of ASD or a set of dimensions; such a subclassification system will be useful for tailoring individual-specific interventions.

Dysregulated protein synthesis underlies several brain disorders, including ASD. In this project, Arkady Khoutorsky will use a mouse model of fragile X syndrome (Fmr1 knockout mice) to examine cell-type-specific alterations in the integrated stress response (ISR) pathway — a pathway that is central to the regulation of protein synthesis in the brain. He will assess the hypothesis that dysregulation of ISR pathway-dependent protein synthesis leads to an altered repertoire of proteins that subsequently contributes to aberrant activity of neuronal circuits and behavioral phenotypes in Fmr1 knockout mice.

Disrupted cerebrospinal fluid (CSF) volume and composition, as well as ventricle formation, are common to many neurodevelopmental disorders, including ASD. Alterations in serotonergic signaling have also been implicated in ASD, yet the sensitivity of the choroid plexus (the primary source of CSF) to serotonin has not been well studied. Maria Lehtinen plans to directly test the consequences of manipulating serotonergic signaling at the choroid plexus. Her team will assess how alterations in serotonergic signaling affect the choroid plexus secretome and cortical development in 16p11.2 deletion mice.

Hirofumi Morishita plans to identify common corticothalamic circuitry deficits in genetic mouse models of autism that affect social behaviors and establish preclinical strategies for ameliorating these social deficits.

Jeremy Veenstra-VanderWeele and colleagues plan to probe the relationship between maternal serotonin levels and neurodevelopmental phenotypes in offspring by assessing serotonin levels in existing maternal blood samples from the Simons Simplex Collection as well as previously collected placental and cord blood samples from a South African cohort.

Sensory hypersensitivity is a central issue in autism and autism-related disorders like fragile X syndrome but relatively little is known about the underlying brain mechanisms. In this project, Richard Salvi plans to combine the use of novel behavioral assays for assessing sound hypersensitivity in rats with state-of-the-art electrophysiological and analytical techniques to determine the nature of auditory perceptual and circuit abnormalities in a rat model of fragile X syndrome.

Converging lines of evidence suggest that dendritic spine pathology is a common feature in ASD. Alex Kwan will use advanced optical imaging methods in awake behaving mice to determine how calcium signaling in dendritic spines is affected by ASD-linked genetic mutations.