Experiments on a Tauopathy Model with Mice Primary Cortical Cultures: the Difficulty of Observing Network Functional Alterations

Tauopathies are a group of neurodegenerative diseases associated to a pathological, hyperphosphorylated state of the microtubule-associated protein tau which, in the brain, cause a progressive degradation of neuronal connections that lead to overt network-wide functional alterations. Despite the importance of these diseases, no in vitro models have explored tauopathies in the context of network dynamics and functional connectivity. To address this gap, here we considered a tauopathy model using mouse primary cultures in which we compared healthy and tau-affected conditions. For that, we prepared control cultures, cultures treated with extracellular wild–type tau, and cultures exposed with pathological tau (pTau) extracted from the sarkosyl–insoluble fraction of P301S (+/-) mice. To accelerate potential pTau-induced damage, cultures were further transduced with viruses encoding P301L human tau. In all culture conditions, spontaneous activity was monitored along 16 days, and different metrics related to network activity and functional characteristics were analyzed. We observed that the presence of pTau did not cause severe disruptions in neuronal network behavior, with only a mild increase in network bursting activity and a slight strengthening of network-wide communication. We hypothesize that the intrinsic properties of primary neuronal cultures, characterized by prevalent network bursting and homeostatic mechanisms, may mask network-level damage, hence making functional alterations difficult to detect.