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.

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.

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.