Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice

- 5xFAD mice are a familial Alzheimer model with profound neocortical layer 5 neurodegeneration.
- Layer 5 neurons in 5xFAD mice are structurally intact up to 14 weeks.
- Synaptic deficits are apparent in layer 5 neurons in young 5xFAD mice and appear before neurodegeneration.
- Our data are consistent with the idea that synaptic loss is the first stage of neurodegeneration and eventual loss in FAD.

Synaptic decay and neurodegeneration are hallmarks of Alzheimer's disease that are thought to precede dementia. Recently, we have reported that the first signs of neuritic dystrophy in a new transgenic mouse model of familial Alzheimer's disease (FAD) called the “5xFAD” are axonal dystrophy followed by loss of spines on basal dendrites. The 5xFAD mouse has profound loss of layer 5 neurons by 12 months, and these initial structural insults appear between 4 and 6 months of age. Here, we test, for the first time, if synaptic failure of layer 5 neurons in the 5xFAD mouse precedes these structural changes. We used longitudinal, in vivo two-photon fluorescence imaging of bigenic 5xFAD/YFP mice to assess the overall structural stability of layer 5 neurons in young mice (age less than 14 weeks). We found these neurons to be structurally and morphologically sound. In parallel, we used in vitro, whole-cell patch clamp electrophysiology of layer 5 pyramidal neurons, from mice aged 8-12 weeks, to reveal significant pre- and postsynaptic defects in these cells. Thus our data suggest that layer 5 neurons in the 5xFAD mouse model have synaptic deficits at an early time point, before any overt structural dystrophy, and that such synaptic failure, with co-temporal biochemical changes, may be an early step in neuronal loss.