Work

Self-Exciting Population Event Models Reveal Abnormal Temporal Amplification in MAPT-Mutant Human Brain Assembloids

Year: 2026

Type: preprint

Abstract: ABSTRACT Human brain assembloids provide a tractable platform for studying mutation-specific network dysfunction, but most studies do not distinguish whether abnormal activity arises from increased spontaneous initiation or stronger history-dependent amplification. We introduce a low-dimensional discrete-time self-exciting population model for calcium-imaging event sequences that separates baseline initiation ( µ ), integrated history-dependent gain ( η ), and memory decay ( τ ). Across 175 recordings from 13 MAPT p.R406W or CRISPR-corrected isogenic assembloids, biological-unit inference identified a 4.31-fold increase in η in mutants (95% CI 3.20–5.84; exact p = 7.8 × 10 − 4 ), without increased baseline activity. Parametric predictive checks exposed residual Poisson overdispersion; fixed-decay and beta-binomial sensitivity analyses nevertheless preserved the mutant history effect. Median η separated all 13 held-out assembloids, while a multifeature recording-level RBF-SVM achieved AUC 0.816 under nested whole-assembloid holdout. These results identify robust history-dependent temporal amplification as a functional MAPT-mutant network phenotype.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.01.756068