A Choroid Plexus Apocrine Secretion Mechanism Modulates Cerebrospinal Fluid Contents and Instructs Cortical Development

Abstract

The choroid plexus (ChP) plays a crucial role in brain development by regulating the composition of cerebrospinal fluid (CSF) and releasing bioactive molecules that shape neural progenitor behavior. However, the full impact of ChP secretory activity on neurodevelopment, particularly during embryonic stages, remains poorly understood. This dissertation investigates a novel apocrine secretion mechanism in the ChP and explores how maternal drug exposure—specifically with serotonergic agents—can perturb ChP function and disrupt cortical development. Our experiments first used the 5HT2C receptor agonist WAY-161503 to directly activate ChP secretion. Ex vivo imaging at embryonic day 14.5 revealed that WAY-161503 triggers robust calcium signaling in ChP epithelial cells, which induces a high-capacity release of proteins into the CSF. Proteomic analysis identified hundreds of proteins involved in essential neurodevelopmental pathways, including SHH, WNT, BMP, and IGF signaling, highlighting the ChP’s potential to influence multiple progenitor populations and cortical development simultaneously. Notably, we found that activating ChP secretion altered progenitor fate, leading to changes in the balance of cortical excitatory neuron populations and disrupting cortical architecture. These findings suggest that precise regulation of ChP secretion is critical for healthy brain development, and disruptions could have long-lasting consequences. Building on these insights, we tested whether maternal exposure to LSD—a serotonergic hallucinogen that acts on 5HT2C and related receptors—would similarly affect ChP function and cortical development. Pregnant mice were administered either acute or repeated doses of LSD, and offspring cortical architecture was assessed postnatally. The LSD-exposed offspring exhibited significant reductions in Tbr1+ deep-layer neurons, altered Satb2+ excitatory neuron populations, and shifts in cortical organization that varied with both sex and exposure regimen. Although we did not perform proteomics after LSD exposure, the observed cortical disruptions align with the hypothesis that serotonergic compounds can alter ChP secretion and downstream neurodevelopmental processes. The behavioral consequences of these cortical changes were also evident, as mice exhibited hyperactivity, increased rotations in the open field test, and disrupted sensorimotor gating, particularly in male offspring. Together, these findings demonstrate the importance of ChP-CSF signaling in neurodevelopment and highlight the risks posed by maternal drug exposure. The disruptions observed with both WAY-161503 and LSD raise concerns about the use of 5HT2C agonists in pregnant populations, especially as several such compounds are currently in clinical development. This work opens new avenues for investigating the broader pharmacological impact of ChP secretion and calls for further research into how the ChP-CSF axis shapes brain development and behavior. Understanding these mechanisms will be essential for identifying potential therapeutic risks and safeguarding healthy brain development.