Prion diseases typically have long pre-clinical incubation periods during which 
time the infectious prion particle and infectivity steadily propagate in the 
brain. Abnormal neuritic sprouting and synaptic deficits are apparent during 
pre-clinical disease, however, gross neuronal loss is not detected until the 
onset of the clinical phase. The molecular events that accompany early neuronal 
damage and ultimately conclude with neuronal death remain obscure. In this 
study, we used laser capture microdissection to isolate hippocampal CA1 neurons 
and determined their pre-clinical transcriptional response during infection. We 
found that gene expression within these neurons is dynamic and characterized by 
distinct phases of activity. We found that a major cluster of genes is altered 
during pre-clinical disease after which expression either returns to basal 
levels, or alternatively undergoes a direct reversal during clinical disease. 
Strikingly, we show that this cluster contains a signature highly reminiscent of 
synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation 
of neuroprotective pathways. Additionally, genes involved in neuronal projection 
and dendrite development were also altered throughout the disease, culminating 
in a general decline of gene expression for synaptic proteins. Similarly, 
deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, 
miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the 
first in depth genomic study describing the pre-clinical response of hippocampal 
neurons to early prion replication. Our findings suggest that prion replication 
results in the persistent stimulation of a programmed response that is mediated, 
at least in part, by synaptic NMDA receptor activity that initially promotes 
cell survival and neurite remodelling. However, this response is terminated 
prior to the onset of clinical symptoms in the infected hippocampus, seemingly 
pointing to a critical juncture in the disease. Manipulation of these early 
neuroprotective pathways may redress the balance between degeneration and 
survival, providing a potential inroad for treatment.