Seizures are a druggable mechanistic link between TBI and subsequent tauopathy

Abstract

Traumatic brain injury (TBI) is a prominent risk factor for neurodegenerative diseases and dementias including chronic traumatic encephalopathy (CTE). TBI and CTE, like all tauopathies, are characterized by accumulation of Tau into aggregates that progressively spread to other brain regions in a prion-like manner. The mechanisms that promote spreading and cellular uptake of tau seeds after TBI are not fully understood, in part due to lack of tractable animal models. Here, we test the putative roles for excess neuronal activity and dynamin-dependent endocytosis in promoting the in vivo spread of tauopathy. We introduce tauopathy reporter zebrafish expressing a genetically-encoded fluorescent Tau biosensor that reliably reports accumulation of human tau species when seeded via intra-ventricular brain injections. Subjecting zebrafish larvae to a novel TBI paradigm produced various TBI symptoms including cell death, hemorrhage, blood flow abnormalities, post-traumatic seizures, and Tau inclusions. Bath application of anticonvulsant drugs rescued TBI-induced tauopathy and cell death; these benefits were attributable to inhibition of post-traumatic seizures because co-application of convulsants reversed these beneficial effects. However, one convulsant drug, 4-Aminopyridine, unexpectedly abrogated TBI-induced tauopathy - this was due to its inhibitory action on endocytosis as confirmed via additional dynamin inhibitors. These data suggest a role for seizure activity and dynamin-dependent endocytosis in the prion-like seeding and spreading of tauopathy following TBI. Further work is warranted regarding anti-convulsants that dampen post-traumatic seizures as a route to moderating subsequent tauopathy. Moreover, the data highlight the utility of deploying in vivo Tau biosensor and TBI methods in larval zebrafish, especially regarding drug screening and intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/091819v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@34a2caorg.highwire.dtl.DTLVardef@1ab916borg.highwire.dtl.DTLVardef@d83bf2org.highwire.dtl.DTLVardef@47bf90_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIntroduces first Traumatic Brain Injury (TBI) model in larval zebrafish, and its easy C_LIO_LITBI induces clinically relevant cell death, haemorrhage & post-traumatic seizures C_LIO_LICa2+ imaging during TBI reveals spike in brain activity concomitant with seizures C_LIO_LITau-GFP Biosensor allows repeated in vivo measures of prion-like tau aggregation C_LIO_LIpost-TBI, anticonvulsants stop tauopathies akin to Chronic Traumatic Encephalopathy C_LI