Hippocampal iPSC-Derived Assembloids to Model Interneuron and Circuit Vulnerability in Genetically-Encoded Amnestic and Behavioral Dementia

from human dementia brains that support an interaction between interneurons, tau toxicity, and cognitive decline. We recently generated hippocampal assembloids in which physiological proportions of interneurons and excitatory neurons — achieved through interneuron migration from the ganglionic eminence — exhibit electrophysiological oscillatory and connectivity properties that mirror those observed in human brain recordings. Mutations in the microtubule-associated protein tau (MAPT), such as R406W and IVS10+16 C>T, cause frontotemporal dementia and result in a spectrum of clinical phenotypes, with a predilection for temporal lobe- dominant syndromes affecting the hippocampus. Human induced pluripotent stem cells (iPSCs) expressing different MAPT mutations exhibit various phenotypes but converge on alterations in genes involved in transsynaptic signaling, including a group of 11 genes enriched in interneurons. Despite these observations, the interaction between MAPT mutations and interneuron subtypes remains poorly understood, due in part to iPSC model systems that lack sufficient numbers of interneurons. By generating human iPSC-derived hippocampal assembloids expressing MAPT mutations, we have developed a unique model of tau mutation-associated toxic phenotypes in a system containing interneurons, excitatory neurons, astrocytes, and simple circuits. This model, once validated, will open opportunities to consider interactions between interneurons, tau toxicity, and circuit-related neuronal dysfunction in mechanistic or drug development applications. We propose to validate this system as a model for studying the interaction of interneurons with MAPT mutation - associated tau toxicity and circuit-related neuronal dysfunction. We will achieve this through reproducibility studies, deeper molecular phenotyping, perturbations of tau mutant expression, and by mapping new phenotypic endpoints achieved by our model to match cellular and physiological data from human MAPT mutation carriers.