Influence of amyloid pathology on retina and dLGN in 5xFAD mouse model

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid beta plaques and neurofibrillary tangles that leads to decreased quality of life due to behavioral, motor, and cognitive impairments.  Due to the widespread pathological nature of AD, many brain regions are affected by amyloid beta plaques including regions important for vision such as the lateral geniculate nucleus (LGN) of the thalamus which is critical for relaying signals from the retina to the primary visual cortex.  Using a wide range of techniques including electrophysiological approaches, in vivo and ex vivo imaging methods, and immunohistochemistry in a mouse model with progressing amyloidosis (5xFAD), the goal of this study was to determine whether AD-like pathology disrupts neuronal and synaptic structure and function in the visual system.  In vivo electroretinogram recordings revealed photoreceptor dysfunction in the 6- and 9-month-old 5xFAD mice, while optical coherence tomography indicated no changes in retinal thickness.  In the dorsolateral geniculate nucleus (dLGN), the rodent homolog of the primate LGN, we identified decreased densities of retinal ganglion cell axon terminals and fewer thalamocortical (TC) neuron cell bodies.  No detectable deficits in excitatory synaptic function or TC neuron dendritic structure were seen in the dLGN, and reflexive visual behavior was also found to be normal in the 5xFAD mice.  These results indicate relatively modest amyloid-triggered dysfunction in these stages of the visual system suggesting that amyloid beta plaque formation may play only a small role in the visual system dysfunction seen in AD patients.  These results may also point to potential compensatory mechanisms that preserve function of visual pathways in the 5xFAD visual system.   

Methods
Immunofluorescence staining, two-photon confocal microscopy: quantifying cell body density, synaptic puncta density

Scotopic electroretinogram (ERG) recording using Celeris Diagnosys small animal ERG system. A- and B-wave amplitudes and oscillatory potentials measured offline in ClampFit. 

Thioflavin-S staining of brain tissue, epifluorescence microscopy, quantifying plaque density in ImageJ

Whole-cell patch-clamp recording from thalamocortical relay neurons in dLGN using Axon/Molecular Devices patch-clamp amplifier (Multiclamp 700A) and data acquisition (DigiData 1550B, Clampex 10), measurement of mEPSCs and mEPSC detection using MiniAnalysis (Synaptosoft)

Neurobiotin cell fills during patch-clamp recording, two-photon confocal imaging, dendritic reconstruction in ImageJ using Simple Neurite Tracer, Sholl analysis

Mouse optomotor response measurements using a custom optomotor measurement system