Functional mapping of the entorhinal cortex reveals a hub for synaptic excitability in the young 3xTg mouse model for Alzheimer's disease

UoM administered thesis: Phd

  • Authors:
  • Francesca Mandino

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, resulting in marked neurodegeneration, cognitive decline, memory loss, emotional and behavioural changes. The traditional pathological hallmarks of AD are insoluble beta-amyloid plaques and hyperphosphorylated protein tau tangles. This results in neurodegeneration and brain atrophy, with early damage in major hubs for cognitive function within the medial temporal lobe, particularly the lateral entorhinal cortex, hippocampal formation and basolateral amygdala. Recently, the focus in AD research has shifted attention from end-stage of the disease to the early asymptomatic (prodromal) stages, where an intricate inter-dependency between the timing of plaque and tangle appearance, together with neuronal plasticity changes, might be the initiating events in AD degeneration. Animal models recapitulate partial aspects of the AD continuum and may help to understand the underlying mechanisms of AD pathogenesis. The 3xTgAD mouse model is an ideal candidate model to investigate early brain changes at the onset of AD-like pathology, in that it is unique in developing both tangles and plaques late in life yet providing an extended time window with only precursor forms of plaques and tangles. Here, early alterations in the synaptic connectivity among key brain regions for AD progression were assessed through electrophysiological recordings in the amygdala and dentate gyrus of male 3xTgAD mice in response to lateral entorhinal cortex stimulation in vivo. We next used longitudinal, whole-brain fMRI to investigate brain-wide functional changes in the 3xTgAD resting-state network. Finally, we used functional mapping of the brain-wide impact of activating entorhinal cortex output by optogenetically exciting entorhinal cortex during simultaneous fMRI recording in 3xTgAD mice. Electrical stimulation of the lateral entorhinal cortex revealed increased fEPSP responses and short-term synaptic plasticity changes in the basolateral amygdala and dentate gyrus in 3-month old male 3xTgAD mice compared to matched controls. These results demonstrate, for the first time, augmented synaptic excitability in the amygdala and ventral dentate gyrus, which is also affected by pathology progression in older mice. Brain-wide assessment of functional connectivity changes revealed network and localised loss in functional connectivity in regions highly involved in episodic memory, emotional processing and reward. The targeting of specific neuronal populations within the entorhinal cortex by means of optogenetic excitation resulted in a potentiated response in 3xTgAD prefrontal and striatal regions compared to age-matched controls at 3 months of age. This work highlights early alterations in synaptic function within and between disease-relevant brain regions in the 3xTgAD mouse by 3 months of age. Clearly decreased functional coupling during resting-state in 3xTgAD, particularly in the entorhinal cortex, was associated in mice of the same age with increased activity in AD-vulnerable brain regions to direct optogenetic activation of the entorhinal cortex. At first sight these results appear to be in contradiction; however, both effects have been reported in AD patients. Here, we propose that they can be resolved by considering a state where there is an overall decrease in inter-regional axonal connectivity that occurs alongside an increase in synaptic strength for the remaining connections in the 3xTgAD model. During endogenous activity, deficits in connectivity could explain the decreased resting-state activity whilst the increased synaptic activity and short-term plasticity produced by exogenous, synchronous activation could potentially explain the apparently incongruous hyperexcitability seen during electrical and optogenetic activation of the entorhinal cortex. Thus, here we demonstrate a brain-wide reorganisation in young 3xTgAD mice, prior to plaques and tangle deposition, in line with clinical evidence and in further support of the 3xTgAD mouse as a valid model for AD.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • John Gigg (Supervisor)
  • Marcelo Montemurro (Supervisor)
Award date1 Aug 2020