Degenerating Synaptic Boutons in Prion Disease

Abstract

A growing body of evidence suggests that the loss of synapses is an early and major component of a number of neurodegenerative diseases. Murine prion disease offers a tractable preparation in which to study synaptic loss in a chronic neurodegenerative disease and to explore the underlying mechanisms. We have previously shown that synaptic loss in the hippocampus underpins the first behavioral changes and that there is a selective loss of presynaptic elements. The microglia have an activated morphology at this stage but they have an anti-inflammatory phenotype. We reasoned that the microglia might be involved in synaptic stripping, removing synapses undergoing a degenerative process, and that this gives rise to the anti-inflammatory phenotype. Analysis of synaptic density revealed a progressive loss from 12 weeks post disease initiation. The loss of synapses was not associated with microglia processes; instead, we found that the postsynaptic density of the dendritic spine was progressively wrapped around the degenerating presynaptic element with loss of subcellular components. Three-dimensional reconstructions of these structures from Dual Beam electron microscopy support the conclusion that the synaptic loss in prion disease is a neuron autonomous event facilitated without direct involvement of glial cells. Previous studies described synapse engulfment by developing and injured neurons, and we suggest that this mechanism may contribute to developmental and pathological changes in synapse numbers.

Microglia: dismantling and rebuilding circuits after acute neurological injury

“…Chronic or Wallerian degeneration in the CNS can occur without microglial processes enveloping synaptic boutons [58, 59]. Additionally, three dimensional reconstructions from both conventional and dual-beam electron microscopy rule out the presence of non-neuronal processes between the pre-synaptic and post-synaptic elements [60]. However, others have suggested that the simple act of collecting tissue maybe enough for microglia to retract from synapses, cofounding results [11].…”

Microdissection and transcriptional profiling

“…8 Electron microscopy studies showed that the degenerating pre-synaptic boutons were found to be progressively enveloped within the post-synaptic density of dendritic spines. 4 Concurrently, morphological changes including swelling and hypertrophy in apparently intact pre-synaptic terminals have also been reported. 9 Importantly, during early disease, the loss of dendrites and the decrease in the number of intact synapses appears to be disproportional to the number of neuronal cell bodies that are lost.…”

“…This process is not uniform throughout the infected brain and may reflect the selective vulnerability of particular neuronal populations based on their intrinsic (genetic components) or extrinsic (local microenvironments) properties. For example, the hippocampus and cortical regions of both humans and animals show the most consistent decrease in synaptic densities in response to infection with various prion strains as quantified by either electron microscopy 4 or by immunohistochemical staining for synaptic markers. 5,6 More specifically, prion patients show abnormalities in synapse organization and morphology, a reduction in the amount of staining of the synaptic protein marker synaptophysin and degeneration of pre-synaptic terminals.…”

“…5,6 More specifically, prion patients show abnormalities in synapse organization and morphology, a reduction in the amount of staining of the synaptic protein marker synaptophysin and degeneration of pre-synaptic terminals. 4,7 In addition to synapse loss, reduction in dendritic spine number is especially noticeable in the stratum radiatum of region 1 of the Cornu Ammonis layer (CA1) of the hippocampus in the majority of murine prion models. Within this region, the degeneration appears to involve both pre-synaptic and post-synaptic components 2 …”

“…2,4 Recent biochemical data has revealed a program of events that defines the loss of synapses. Initially, proteins implicated in the pre-synaptic terminal compartment, particularly those involved in synaptic vesicles, were decreased.…”