P23 Investigating synaptopathy following traumatic brain injury in a preclinical model

Abstract

ObjectivesThe impact of Traumatic Brain Injury (TBI) on the synapse is poorly understood. We examined the impact of TBI on the distribution of two postsynaptic density proteins (PSD95 and SAP102) at single-synapse resolution.Subjects44 male transgenic knock-in mice, aged 8–16 weeks, expressing fluorescently labelled PSD95 and SAP102.MethodsMice were randomised to a mild lateral fluid percussion injury (LFPI) or sham treatment and brain sections were examined at 7 and 28 days. Using high resolution confocal microscopy and machine learning algorithms, the synaptic puncta density, size and intensity were mapped across 222 brain regions. Microglia and presynaptic changes were indexed using Iba1 and SV2A immunostaining. Pearson correlation and t-tests were used (significance p<0.05).ResultsWe found a significant reduction in synaptic puncta density at 28 days post-injury in brain regions distal to the injury site including the hippocampus. PSD95 and SAP102 density changes had a strong positive correlation at 28 days (r=0.8; p<0.0001). We also observed evidence of synapse recovery in the ipsilateral cortex between 7 and 28 days. Puncta density had a positive correlation with SV2A (r=0.7; p<0.01) and a negative correlation with (r=−0.6; p<0.001) Iba1 count.ConclusionsFocal LFPI induced progressive region-specific loss of synapses for which microglia may play a role. Our study highlights the value of brain-wide synaptome mapping technology and suggests a capacity for synaptic recovery which could be a therapeutic target.