Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression

Jang, S.-S.; Tabuena, D. R.; Grone, B.; Yip, O.; Blumenfeld, J.; Koutsodendris, N.; Ding, L.; Xu, Q.; Yoon, S. Y.; Huang, Y.; Zilberter, M.

doi:10.1101/2023.08.28.555153

bioRxiv · 10.1101/2023.08.28.555153

Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression

Jang, S.-S.·Tabuena, D. R.·Grone, B.·Yip, O.·Blumenfeld, J.·Koutsodendris, N.·Ding, L.·Xu, Q.·Yoon, S. Y.·Huang, Y.·Zilberter, M.

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Abstract

The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimers disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

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Jang, S.-S., Tabuena, D. R., Grone, B., Yip, O., Blumenfeld, J., Koutsodendris, N., Ding, L., Xu, Q., Yoon, S. Y., Huang, Y., Zilberter, M.. 2023-08-29. Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression. https://doi.org/10.1101/2023.08.28.555153

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