Brain Region Specific Pre-Synaptic and Post-Synaptic Degeneration Are Early Components of Neuropathology in Prion Disease

Abstract

Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.

Early Hippocampal Synaptic Loss Precedes Neuronal Loss and Associates with Early Behavioural Deficits in Three Distinct Strains of Prion Disease

“…As previous terminal stages studies would have predicted, there is some cerebellar tropism in the 22L strain that is not obvious in ME7 and 79A strains, and indeed 22L shows somewhat weaker synaptic loss, microglial activation and PrP Sc deposition in the CA1 of the hippocampus with respect to the dentate gyrus/CA3 region. However, that 22L can produce CA1 synaptic loss is significant, and this has now been confirmed by electron microscopy studies [22]. On the whole 79A produces rather similar early pathology to ME7.…”

How structure shapes (dys)function

“…In contrast to early synaptic changes in the stratum radiatum of the hippocampus, which are virtually identical to those detected with a different prion strain (ME7), 3 dendritic rather than synaptic disintegration was observed in the cerebellum, even in late-stage disease. Similar levels of protease-resistant pathological prion protein have been found in the hippocampus and in the cerebellum of ME7 and 22L prion strains 2 , 4 . In Creutzfeldt-Jakob disease, the most common prion disease in humans, cerebellar alterations are well documented; 5 notably, flattening and reduction of dendritic arbors of Purkinje cells have been reported 6 .…”

“…Degenerative changes associated with the Purkinje cells were dominated by dendritic malformations, while the major synaptic inputs to the cerebellum were preserved. Electron microscopy confirmed that the spiny branchlets on Purkinje neurons and the parallel and climbing fiber terminals were both intact, whereas the Purkinje dendrites degenerated progressively 2 . We concluded that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.…”

“…In our recent study, we demonstrated that, within a brain undergoing chronic neurodegeneration, region-selective processes involve distinct neuronal compartments. Following a focal brain injection of the mouse-adapted 22L scrapie prion strain, the ultrastructure of the hippocampus and the cerebellum revealed that synaptic loss is not a ubiquitous outcome of chronic brain insult 2 . In contrast to early synaptic changes in the stratum radiatum of the hippocampus, which are virtually identical to those detected with a different prion strain (ME7), 3 dendritic rather than synaptic disintegration was observed in the cerebellum, even in late-stage disease.…”

“…The hippocampus and the cerebellum are both structurally regular, with a well-defined synaptic circuitry; unmyelinated parallel axons innervating Purkinje neurons in the cerebellum and CA1 pyramidal neurons in the hippocampus are both glutamatergic, and both contact dendrites of the principal cells via dendritic spines 3 , 9 . Using either of the prion strains, the glutamatergic, asymmetric type I synapses in the stratum radiatum of CA1 were selectively reduced in their numbers in comparison to age-matched controls 2 , 3 . The synaptic terminals and their postsynaptic sides degenerated, with clear-cut abnormalities detected at 12 weeks postinjection, and without other obvious ultrastructural signs of degeneration in CA1 or CA3 neurons 10 .…”