FUNCTIONAL CHARACTERIZATION OF NEURONAL ACTIVITY AND SYNAPTIC PLASTICITY IN FOREBRAIN AND HIPPOCAMPAL-LIKE ORGANOIDS

In recent years, many new human IPSC-derived brain organoid models have been created, providing an opportunity to depart from animal-based models and study human-like molecular and physiological mechanisms of brain functions.
Here we use high-density multi-electrode array (HD-MEA) recordings to compare forebrain and hippocampal-like organoids – generated by optogenetic WNT3A overexpression – derived from two donor lines. Forebrain organoids were more active compared to their hippocampal-like counterparts. Hippocampal-like organoids from both donor lines showed a higher response to gabazine compared to the forebrain organoids, indicating a more prominent inhibitory network.
In preliminary tests in one donor line (TISSUi006-A), we induced chemical long-term potentiation (LTP) with glycine. Both forebrain and hippocampal-like organoids showed potentiation for at least 2.5 hours after induction, suggesting they are capable of long-term synaptic plasticity.
Using VisiumHD spatial transcriptomics, we captured the spatial distribution of differentially expressed genes in both organoid types at 90 minutes post chemical LTP induction. Expression of immediate early genes, and synapse function and plasticity-related genes were increased in both forebrain and hippocampal-like organoids following potentiation with glycine, compared to non-stimulated controls. Interestingly, hippocampal-like organoids expressed higher levels of immediate early genes than forebrain organoids. Single-nuclei transcriptomics of late LTP, 2.5 hours after induction, is in progress. These findings can provide new human centered treatment approaches for understanding and treating cognitive disorders that affect synaptic plasticity.