Hyperexcitability in FTLD patient neurons

Abstract

Mutations in the gene MAPT encoding tau, a microtubules–associated protein, cause a subtype of familial neurodegenerative disease, known as frontotemporal lobar degeneration tauopathy (FTLD–Tau). We modeled FTLD–Tau using FTLD–Tau patient iPSCs. FTLD–Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death. FTLD–Tau neurons showed dysregulation of the augmentation of Ca²⁺ transients evoked by electrical stimulation. The introduction of designer receptors exclusively activated by designer drugs (DREADDs) or the treatment with glutamate receptor blockers attenuated misfolded tau–related neurodegeneration (Imamura et al., Sci Rep., 2016). These data suggest that neuronal hyperexcitability may regulate neurodegeneration in tauopathy. This FTLD–Tau model provides a useful tool for tauopathy treatments.