Human neurogenesis extends well into the postnatal period, characterized by massive streams of interneurons migrating into specific cortical regions such as the entorhinal cortex. We have successfully modeled this protracted human-specific process in long-term organoid cultures, recapitulating the complex glia-guided migratory architecture observed in infant human brains. Using spatial transcriptomics and mathematical modeling, we identify key receptor-ligand interactions between migrating neurons and surrounding astrocytes. We utilize functional assays and human assembloid models to investigate whether subtle disruptions in postnatal interneuron migration contribute to the pathogenesis of Autism Spectrum Disorders (ASD).
Understanding how diverse neurodevelopmental risk genes impair cell specification and migration requires systematic functional testing directly in human tissue. Building on our CRISPR-LICHT and CHOOSE screening technologies, we perform inducible, barcoded single-cell loss-of-function screens in organoids to interrogate gene regulatory networks controlled by key Autism Spectrum Disorder (ASD) susceptibility genes (such as OLIG1 and EOMES). Combining the CHOOSE framework with human assembloid models allows us to evaluate cell fate specification, migration, and tissue development directly within complex human tissue architectures, enabling high-throughput mapping of phenotype-to-gene relationships across specific cell types.
Neurodevelopmental conditions are ultimately defined by alterations in functional neural network activity. Using high-density silicon electrode arrays, we capture complex oscillatory network dynamics in cerebral organoids and validate them against clinical extracellular recordings from patients. In models of Tuberous Sclerosis Complex (TSC) and epilepsy, we investigate how hyperactive mTOR signaling drives the overproliferation of specific cell types—such as human CLIP cells—and alters high-frequency electrical burst dynamics. By mapping these electrical phenotypes back to specific neuronal populations, we establish organoid electrophysiology as a predictive platform for identifying disease biomarkers and evaluating candidate therapeutic interventions.
We map the connectome of healthy and diseased organoids at single-cell resolution using novel virus-based trans-synaptic labeling techniques. By barcoding retrogradely spreading rabies viruses and combining them with single-cell RNA sequencing, we identify synaptic connections between specific neuronal cell types. This groundbreaking approach allows us to pinpoint changes in synaptic connectivity in disease models—such as Tuberous Sclerosis Complex (TSC)—and identify key target genes that mediate these alterations. Over the coming years, we will apply this technology to uncover the fundamental connectivity phenotypes underlying severe neurodevelopmental disorders, including Coffin–Siris syndrome and Dravet syndrome, opening new therapeutic avenues.
