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

Epileptic activity in mouse models of Alzheimer’s disease requires the protein tau, and in the October 19 Cell Reports, Lennart Mucke and colleagues at the Gladstone Institute of Neurological Disease, San Francisco, describe how tau contributes to such overly synchronized neural discharges. In mice lacking tau, cortical excitatory neurons fired less often, while inhibitory neurons fired more. In culture, neurons sans tau resisted electrical and chemical excitation. In mixed cultures of excitatory and inhibitory neurons, absence of tau kept inhibitory outputs high and synchronous activity low even under excitatory pressure.

  • Without tau, excitatory neurons become less active.
  • Inhibitory neurons fire more action potentials.
  • The net effect is to dampen network activity, protecting against hyperexcitability.

“The changes in excitatory and inhibitory neurons all point in the same direction, of making the network more resistant to hyperexcitability,” Mucke noted. “Tau reduction seems to be a safety valve that prevents overstimulation under a variety of conditions.” Tau reduction is already being explored as a therapeutic strategy, thus far without success (Jul 2019 news; Jun 2021 news). Researchers are targeting antibodies at tau and are testing whether tau antisense oligonucleotides can prevent neurofibrillary tangles in AD and primary tauopathies.

Others said the data make an important contribution. “This work is a clear advance in our understanding of how tau proteins sculpt the excitability of neuronal networks,” Jeffrey Noebels at Baylor College of Medicine, Houston, wrote to Alzforum (full comment below). Günter Höglinger at Munich's Technical University said, “The change in neuronal activity patterns induced by tau-lowering strategies is an exciting new finding that holds promise for the treatment of epilepsies.”

Not Excited. Tau knockouts (right, green) have less excitatory (top) and more inhibitory (middle) activity than do wild-types (left, gray). In toto, they better resist excitatory stimuli and avoid hypersynchrony (bottom). [Courtesy of Chang et al., Cell Reports.]

Previous work by Mucke and others demonstrated that, surprisingly, removing tau curbed excitotoxicity in mouse models of AD and epilepsy (May 2007 news; Jan 2011 news; Jan 2013 news). Exactly how that happened was unknown, however.

First author Che-Wei Chang investigated the mechanism in cortical slice cultures from tau knockout mice. Chang found that excitatory pyramidal cells popped off fewer action potentials than their wild-type counterparts, although their firing threshold was the same. Inhibitory interneurons, on the other hand, had a lower firing threshold than their wild-type counterparts, and as a result were more electrically active. The overall effect was to tilt the slices' excitation/inhibition balance toward inhibition.

“The differential effects on excitatory and inhibitory neurons is a surprising finding,” noted Lars Ittner at Macquarie University, Sydney (comment below). Mucke believes the change may start in excitatory neurons, which rein in their activity in response to tau loss. This would reduce inputs to inhibitory interneurons, in theory dropping their activity, but Mucke believes that loss of stimulation triggers interneurons to instead boost their output to compensate. Such a compensatory response could be adaptive, since the brain needs a certain amount of inhibitory signaling to maintain crucial functions such as gamma oscillations. The greater inhibitory output would then further suppress excitatory cells. “Tau reduction starts a [feedback] loop that constrains the network in beneficial ways,” Mucke told Alzforum.

Devoid of tau, inhibitory interneurons stopped dialing down their activity. In isolated cell cultures, wild-type interneurons become less active under depolarizing conditions, shortening their axon initial segment (AIS) and shifting it farther away from the cell body. The AIS is responsible for generating action potentials; it is more active when it is longer and closer to the soma (Grubb et al., 2011). Tau knockout interneurons maintained an active, long AIS even under depolarizing conditions. Likewise, knockout cultures of excitatory and inhibitory neurons kept up their respective activities even when subjected to external excitation, whereas wild-type cultures aligned their firing patterns into hypersynchronous rhythms.

In future work, Mucke will selectively lower tau in excitatory or inhibitory neurons to more finely dissect the contributions of each cell type and explore the molecular mechanisms. He noted that an elevated excitatory/inhibitory ratio marks many diseases besides AD, including epilepsy, stroke, autism, stress-induced depression, and traumatic brain injury. “Tau reduction counteracts aberrant shifts in E/I ratios, and is of potential benefit in many diseases,” Mucke said. So far, tau reduction has shown no detrimental effects in wild-type mice and nonhuman primates, and also appeared safe in the Phase 1 trial of an ASO that dropped tau levels in the cerebrospinal fluid by half (Aug 2021 conference news). 

The scientists all agreed that more research is needed to learn if tau reduction would be beneficial in adult human brain, and whether it might alter the function of other cell types such as astrocytes and microglia in potentially undesirable ways. “This phenomenon needs to be carefully monitored in future clinical trials, including electrophysiological and clinical monitoring,” Höglinger said.—Madolyn Bowman Rogers

Comments

  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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References

News Citations

  1. AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy
  2. Biogen Shelves Gosuranemab After Negative Alzheimer’s Trial
  3. APP Mice: Losing Tau Solves Their Memory Problems
  4. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication
  5. One Protein Fits All? Non-AD Epilepsy Models Thrive Sans Tau
  6. Antisense Therapy Stifles CSF Tau in Mild Alzheimer’s Disease

Paper Citations

  1. Grubb MS, Shu Y, Kuba H, Rasband MN, Wimmer VC, Bender KJ. Short- and long-term plasticity at the axon initial segment. J Neurosci. 2011 Nov 9;31(45):16049-55. PubMed.

Further Reading

Primary Papers

  1. 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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