Stereotaxic Delivery of M1000 Prions to the Hippocampus Induces Related Behavioural and Cognitive Changes Consistent...

Prion diseases are fatal neurodegenerative disorders characterised by the misfolding of the normal prion protein (PrP^c) into a pathogenic isoform (PrP^Sc), with the latter constituting the predominant or possibly only component of infectious prions. While ongoing PrP^Sc propagation and accumulation appear central pathophysiological features underpinning disease progression, whether PrP^Sc harbours direct acute neurotoxic effects in vivo has been under-investigated. In this study, we aimed to investigate the hypothesis that PrP^Sc in sufficient quantity can induce acute neurotoxicity in vulnerable brain regions independent of significant net transmitting PrP^Sc replication. Using the M1000 prion mouse model, known for its early hippocampal involvement, we assessed for related motoric, behavioural and cognitive changes over a 7-to-16-day window following stereotaxic hippocampal inoculation. Histological interrogation verified anatomically correct delivery of M1000 prions. Notably, we observed significant reductions in exploratory behaviour in the open field test, with the Y-maze and Barnes maze showing M1000 inoculated mice to have subtle deficits in novelty preference and spatial memory during initial testing phases, respectively. Fear conditioning revealed intact associative fear learning but impaired extinction of conditioned stimulus (CS) responses at 48 h post-conditioning. Rotarod performance and other assessments excluded co-incidental gross motor deficits as a confounder in behavioural and cognitive assessments. These findings suggest that exposure to brain homogenates harbouring abundant M1000 prions can induce prompt changes in behaviour and cognition consistent with acute neurotoxicity in brain regions like the hippocampus vulnerable to the specific prion strain, within a timeframe wherein substantial net transmitting PrP^Sc replication is not occurring as reflected by prominently declining infectivity titres. Our results are compatible with the hypothesis that at least some PrP^Sc species in terminal M1000 brain homogenates harbour intrinsic direct neurotoxicity but cannot exclude contributions from other factors such as cytokines, with overt manifestation probably dependent on regional vulnerability of neurons and consequent pathophysiological thresholds, as well as utilisation of relevant, sufficiently sensitive assessment methods.