Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s

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In Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD. Here we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K + channels, but not changes in mRNA expression, are responsible for dampened excitability. These K + conductances could efficiently regulate near-threshold AP firing, resulting in gamma-frequency specific network hyperexcitability. Our findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.

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  1. Evaluation Summary:

    Using computational modeling and dynamic clamp recordings, this work supports the concept that hyperexcitability of cortical circuits in a familial mouse model of Alzheimer's disease is caused by impairments of biophysical properties of Kv3 channels in parvalbumin-positive cortical interneurons. Overall, the work is clear and interesting but some further analysis is required to provide compelling support to the central claims.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

  2. Reviewer #1 (Public Review):

    This manuscript describes the finding that the voltage-dependence and kinetics of one component of K+ current in parvalbumin positive cortical interneurons in a mouse model of Alzheimer's disease (5xFAD) is different from that in the same neurons of wild type mice. Using computational modeling and dynamic clamp recordings, the work supports the concept that this alteration in K+ current reduces the firing rate of these inhibitory interneurons in response to weak stimulating currents, and that this may lead to the overall hyperexcitability of cortical circuits in the 5xFAD model. The work then goes to make two major claims about the nature of the change in K+ current: i) that the change in voltage-dependence and kinetics does not involve any change in the expression of K+ channels and ii) that it represents a posttranslational modification of Kv3 channels that alters their biophysical properties. Overall, the work is clear and interesting but more would be required to substantiate these two claims.

    1. The possibility that different levels of channel subunits or their auxiliary subunits exist in the wild type mice and the 5xFAD mice has not been ruled out.

    2. It has not been established completely that the component of current that differs between the two strains of mice solely represents the activity of Kv3 channels.

    3. While many posttranslational mechanisms linked to cellular signaling pathway are known to modify Kv3 channels, and some of them could account for the observed differences, none of these are tested or discussed in the manuscript.

  3. Reviewer #2 (Public Review):

    In this study, the authors used a viral-tagging method to compare in the somatosensory cortex, the excitability of parvalbumin (PV) interneuron of young adult 5xFAD mice (an early-stage Alzheimer's disease [AD] mouse model) and WT mice. In current clamp recording from cortical slices, they found that PV interneurons from 5xFAD mice displayed strongly dampened spike discharge near-threshold and modified action potential (AP) waveforms. Extensive examination of several AP firing parameters, computational modeling, and PV-specific qPCR experiments indicated that changing Na+ channel availability was not responsible for the changes in AP firing. Outside-out patch-clamp recording and quantitative qPCR revealed alterations in the voltage dependence of Kv3 K+ channel activation and kinetics in AD mice, without significant changes in K+ channel gene expression. Using dynamic clamp and PV interneuron modeling, they found that the left-shift in Kv3 channel activation could recapitulate the observed firing phenotypes in 5xFAD mice with a near-threshold hypoexcitabilty of PV interneurons. Kv3 modulation reduces synaptically-evoked AP firing in PV interneurons. Using a reduced cortical network model, the authors showed that the changes in PV interneuron firing induced by Kv3 channel biophysical alterations were sufficient to produce gamma-frequency specific network hyperexcitability.

    The work deciphers in detail the intrinsic excitability properties of PV interneurons, which allowed the identification of an interesting difference in the biophysical properties of the predominant Kv3 current of AD mice (5xFAD) as compared to WT mice. Exploiting the state-of-the-art dynamic clamp technique and cortical network modeling, the authors could elegantly reproduce the firing features of AD mice and examine their consequences to cortical network hyperexcitability. This work represent an interesting cellular mechanism with a causal link to overall circuit hyperexcitability, with a potential therapeutic approach to combat AD progression in its early stages.

    Although the work exhibits the strength principles, it suffers from insufficient and sometimes inappropriate analyses that are necessary to fully support the key claims of the manuscript. In addition, plausible alternative explanations related to the firing features of AD mice and their cellular mechanism need to be considered. Therefore, some aspects of the experiments and data analyses need to be extended and clarified.