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These processes are of enormous clinical relevance as they hold the key to identification of new molecular targets for therapeutic intervention. In this review, we will discuss two broad areas of investigation relevant to understanding prion neurotoxicity. The first is the use of <jats:italic>in vitro<\/jats:italic> experimental systems that model key events in prion pathogenesis. In this context, we will describe a hippocampal neuronal culture system we developed that reproduces the earliest pathological alterations in synaptic morphology and function in response to PrP<jats:sup>Sc<\/jats:sup>. This system has allowed us to define a core synaptotoxic signaling pathway involving the activation of NMDA and AMPA receptors, stimulation of p38 MAPK phosphorylation and collapse of the actin cytoskeleton in dendritic spines. The second area concerns a striking and unexpected phenomenon in which certain structural manipulations of the PrP<jats:sup>C<\/jats:sup> molecule itself, including introduction of N\u2010terminal deletion mutations or binding of antibodies to C\u2010terminal epitopes, unleash powerful toxic effects in cultured cells and transgenic mice. We will describe our studies of this phenomenon, which led to the recognition that it is related to the induction of large, abnormal ionic currents by the structurally altered PrP molecules. Our results suggest a model in which the flexible N\u2010terminal domain of PrP<jats:sup>C<\/jats:sup> serves as a toxic effector which is regulated by intramolecular interactions with the globular C\u2010terminal domain. Taken together, these two areas of study have provided important clues to underlying cellular and molecular mechanisms of prion neurotoxicity. Nevertheless, much remains to be done on this next frontier of prion science.<\/jats:p>","DOI":"10.1111\/bpa.12694","type":"journal-article","created":{"date-parts":[[2018,12,27]],"date-time":"2018-12-27T04:54:45Z","timestamp":1545886485000},"page":"263-277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Prion neurotoxicity"],"prefix":"10.1111","volume":"29","author":[{"given":"Nhat T. 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