Friday, May 9, 2025
5/9/2025
Transcriptomic and Proteomic Analysis of Tau-dependent E/I Imbalance - SUMMARY Evidence for excitation/inhibition (E/I) imbalance of neural networks has been found in diverse brain disorders that are prevalent, devastating, and refractory or poorly responsive to available therapies, including Alzheimer’s disease (AD), epilepsy, and autism spectrum disorders. In animal models for these conditions, reducing overall levels of non-aggregated, endogenous, wildtype tau prevents or diminishes disease manifestations triggered by diverse causes, ranging from the neural accumulation of amyloid proteins to mutations in genes encoding sodium or potassium channels, stroke, and the pharmacological blockade of neurotransmitter receptors. Since all of these abnormalities promote E/I imbalance and network hyperexcitability, which can disrupt important processes required for the health of neurons and other brain cells, we hypothesize that the reduced E/I ratio in tau-deficient brains explains, at least in good part, the broad therapeutic benefits of overall tau reduction. Here, we propose to explore the underlying molecular mechanisms by combining cell type-specific tau ablation and chemically induced E/I imbalance with molecular profiling analyses focused on excitatory forebrain neurons. Previous studies have revealed that tau can bind to or interact with a plethora of other proteins. Because many, if not most, of these tau-interacting proteins have the potential to affect neuronal activities, the primary mechanisms by which tau enables and tau reduction counteracts network hyperexcitability remain to be determined. In light of our recent discovery that selective ablation of tau in excitatory, but not inhibitory, neurons is sufficient to counteract E/I imbalance, we hypothesize that these mechanisms can be revealed by comparing the molecular profile of excitatory neurons that do or do not express tau before and during the emergence of chemically induced network hyperexcitability. We propose to test this hypothesis at the mRNA level (Aim 1) and at the protein level (Aim 2). Because of complementary strengths and weaknesses of these approaches and our related experimental designs, we further hypothesize that an integrative analysis of the resulting datasets (Aim 3) has the best chance to pinpoint the most critical mechanisms by which tau enables and tau reduction counteracts the development of E/I imbalance under pathological conditions. Identifying these mechanisms could provide new insights into the pathobiology of tau, help guide the development and evaluation of tau-targeting therapeutics, and result in the identification of additional indications and drug targets.
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