Building the cerebral cortex requires the orchestration of molecular signals spatially synchronized across neural progenitor cells. During early stages of mammalian brain development, the entire brain forms around cerebrospinal fluid (CSF)-filled ventricles. Previous studies by Maria Lehtinen and colleagues have revealed that, early on, secreted signals in the CSF promote neural stem cell identity and health. Disrupted CSF volume and composition, as well as ventricle formation, are common to many neurological conditions, including autism spectrum disorder (ASD). Specifically, elevated levels of CSF have been found in ASD. Lehtinen’s team has been investigating how alterations in CSF contribute to ASD, including work supported by a previous SFARI award that assessed links between maternal immune activation and changes in CSF composition in a mouse model of autism.
The choroid plexus, a sheet of epithelial cells located in each brain ventricle, is considered the primary source of CSF. However, very little is known about the basic mechanisms regulating the choroid plexus secretome. Clues to answering this question may be found in the availability of neuromodulators that are distributed in the CSF. Serotonergic signaling is known to play important roles in the development and health of the brain, and imbalances in the system during fetal development are associated with a growing number of conditions, including ASD. Therapeutic intervention/supplementation with serotonin (5-HT) affects many targets in the brain. Yet the sensitivity of the choroid plexus to natural and augmented levels of 5-HT has been largely overlooked in neurodevelopmental disease research.
Lehtinen’s laboratory hypothesizes that the secretion of CSF by the choroid plexus is affected by 5-HT signaling. Her team plans to assess how alterations in 5-HT levels regulate the choroid plexus secretome and the availability of health and growth-promoting factors in the developing brain. These experiments will use 16p11.2 deletion mice, which have been shown previously to have altered serotonergic signaling1,2. Lehtinen’s group will test if augmenting serotonergic signaling at the embryonic choroid plexus can partially alleviate the cortical disruptions observed in this ASD model and if such improvements correlate with a restoration of normal secretion of factors by the choroid plexus. These findings should have major implications for the treatment of neurodevelopmental conditions such as ASD and for understanding potentially deleterious effects of maternal drugs that alter serotonergic signaling in the brain (e.g., selective serotonin reuptake inhibitors that are prescribed for depression and anxiety disorders) on fetal choroid plexus function and CSF production.