Evidence of prodromal neuronal hyperexcitability and neuroinflammation in a rodent model of human alpha-synucleinopathy

There is growing evidence that patients with dementia with Lewy bodies exhibit early cortical network excitability and neuroinflammatory changes. To explore the link between the two we have used a transgenic mouse that expresses human mutant alpha-synuclein (hA30P). The study investigated whether there were early pre-symptomatic, neuroinflammatory changes in hA30P mice that could contribute to the network hyperexcitability previously observed.Studies were conducted using 1 month and 2-4 months old hA30P mice of both sexes and compared to age-matched wild-type (WT) mice. Fixed, frozen hippocampus sections were immunofluorescently stained using antibodies against c-fos (a marker of neuronal activity), GFAP (for reactive astrocytes), and Iba-1 and iNOS (for reactive microglia). Sections were imaged and densitometric analysis was conducted using Fiji software and analysed using nonparametric tests.Measurements were made in the CA3 hippocampal region. There was significantly increased expression of c-fos in hA30P mice compared to WT at 1 month, consistent with neuronal hyperexcitability, but a downregulation at 2-4 months age, possibly due to chronic network hyperexcitability. In addition, in both age groups and both sexes, there were significant increases in the % area of GFAP immunofluorescence per section and an increase in the proportion of Iba-1+ microglia co-expressing iNOS in hA30P (86%) versus WT mice (6%, p˂0.01) suggesting more reactive astrocytes and reactive microglia respectively.Overall, we have found evidence for early changes in neuronal activity and neuroinflammatory markers in the CA3 hippocampal region in young hA30P mice, occurring well before the onset of cognitive dysfunction.