Chang CW, Evans MD, Yu X, Yu GQ, Mucke L. Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony. Cell Rep. 2021 Oct 19;37(3):109855. PubMed.

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  1. This work is a clear advance in our understanding of how tau proteins sculpt the excitability of neuronal networks. In tau-deficient mouse brain, the authors find a selective increase in intrinsic interneuron excitability, leading to elevated levels of synaptic inhibition, while the firing properties of excitatory cells is largely spared. This imbalance is consistent with the striking evidence that tau gene deletion in a host brain corrects abnormal network hypersynchrony in AD and several other mouse epilepsy models, even including the seizure onset zone in the peritumoral microenvironment of glioblastoma (Hatcher et al., 2020).

    But will lowering tau protein in the adult AD brain be sufficient to reverse hyperexcitability? As the authors point out, acutely lowering tau protein at older ages was not studied here. In addition, the effects of global tau suppression may alter the function of other cell types like astrocytes, microglia, and oligodendrocytes that play complex roles in AD progression, with potential untoward consequences. 

    A unexpected and novel finding is the importance of tau in maintaining the anatomical integrity of the axon initial segment (AIS), where action potentials arise. Interneurons without tau protein showed a blunting of structural plasticity leading to altered thresholds for spike initiation. While the molecular interactions of tau in this vital axon compartment remain to be examined, it is worth noting that mutation of other scaffolding proteins (ankyrins and spectrins) that tether key ion channels (Scn8a, Kv1) also lead to epilepsy, designating the AIS as a "hotspot" for network hypersynchrony.

    References:

    Hatcher A, Yu K, Meyer J, Aiba I, Deneen B, Noebels JL. Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model. J Clin Invest. 2020 May 1;130(5):2286-2300. PubMed.

    View all comments by Jeffrey L. Noebels

  2. This nice study adds yet more information on the effects of depleting tau in mice. The differential effects on excitatory and inhibitory neurons is a surprising finding. Therapies that target the reduction of tau may require tailored targeting of neuronal cell types. Whether these findings translatable into human (e.g. iPSC) remains to be shown.

    One should also keep in mind that different effects of tau reduction have been observed in different genetic mouse backgrounds (Bi et al., 2017; Tuo et al., 2017), suggesting that confounding factors of mediating the effects of tau reduction are yet to be identified.

    I agree with the authors that the effect of partial tau reduction in Mapt+/- would be interesting to investigate in order to gauge whether therapies targeting tau reduction may need to be reconsidered.

    References:

    Bi M, Gladbach A, van Eersel J, Ittner A, Przybyla M, van Hummel A, Chua SW, van der Hoven J, Lee WS, Müller J, Parmar J, Jonquieres GV, Stefen H, Guccione E, Fath T, Housley GD, Klugmann M, Ke YD, Ittner LM. Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun. 2017 Sep 7;8(1):473. PubMed.

    Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Li XL, Liuyang ZY, Roisman L, Zhang ST, Ayton S, Wang Q, Crouch PJ, Ganio K, Wang XC, Pei L, Adlard PA, Lu YM, Cappai R, Wang JZ, Liu R, Bush AI. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017 Nov;22(11):1520-1530. Epub 2017 Sep 8 PubMed.

    View all comments by Lars M. Ittner

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  1. Lowering Tau Tips the Brain's Balance of Excitation/Inhibition