Abstract
Therapeutic developments for neurodegenerative disorders are redirecting their focus to the mechanisms that contribute to neuronal connectivity and the loss thereof. Using a high-throughput microscopy pipeline that integrates morphological and functional measurements, we found that inhibition of dual leucine zipper kinase (DLK) increased neuronal connectivity in primary cortical cultures. This neuroprotective effect was not only observed in basal conditions but also in cultures depleted from antioxidants and in cultures in which microtubule stability was genetically perturbed. Based on the morphofunctional connectivity signature, we further showed that the effects were limited to a specific dose and time range. Thus, our results illustrate that profiling microscopy images with deep coverage enables sensitive interrogation of neuronal connectivity and allows exposing a pharmacological window for targeted treatments. In doing so, we revealed a broad-spectrum neuroprotective effect of DLK inhibition, which may have relevance to pathological conditions that ar.e associated with compromised neuronal connectivity.
Highlights
Wiring the central nervous system demands precise formation and maintenance of neuronal connections
Up to 36 days in vitro (DIV), the neuronal network became denser, as exemplified by an increase in dendrite network density and the number of nodes in the network (Fig. 2b)
This multiparametric analysis showed that cortical neurons develop progressive morphological connectivity up to 36 DIV with the strongest evolution taking place between 3 and 18 DIV
Summary
Wiring the central nervous system demands precise formation and maintenance of neuronal connections. Synaptic activity and the adjoined opening of gated calcium channels generate calcium transients that drive morphological changes such as dendritic growth and arborization, but which can influence synapse strength [2] This dynamic remodeling of both neurites and synapses fosters improved communication between neurons allowing synchronous functional activity, thereby. As yet, primary neuronal cultures represent the model of choice for genetic and pharmacological highthroughput screens [3, 6, 8, 9, 28, 31, 43, 53, 55] Most of these screens tend to focus on one or two specific readouts such as neuron number [6, 31], neurite outgrowth [3, 6, 8, 31] or synapse density [53, 55]. We identified dual leucine zipper kinase (DLK) inhibition as a positive modulator of neuronal connectivity in unperturbed cultures and as a neuroprotector in cultures grown under suboptimal or compromised conditions
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