Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer’s disease

Abstract

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer’s disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer’s disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

Lipopolysaccharide-induced neuroinflammation disrupts functional connectivity and community structure in primary cortical microtissues

“…Coordinated neural network activity is paramount to a healthy functioning brain and an important feature to examine in vitro. Numerous studies have demonstrated the utility of functional characterization in capturing underlying neural activity during development and disease both in vivo and in vitro 3,7,15,[19][20][21][22][23][25][26][27][28][29][30] . Because neural cell behavior emerges from the development of complex interconnected networks, extending the functional analysis to include network-wide activity is essential to understanding functional dynamics in vitro.…”

“…Changes in microcircuit community structure is an indicator of neural dysfunction associated with memory deficits 26,28 . Here, we investigated the influence of LPS-induced acute neuroinflammation on modularity and the underlying community structure of microcircuits in vitro.…”

“…Calcium imaging is particularly well-suited to the in vitro environment because cultured neurons are not optically obstructed by the meninges or skull as they are in vivo. Calcium imaging has been used in vitro to examine functional neural behavior under controlled conditions to study both development and disease 3,7,23,[26][27][28][29][30] .…”

“…At the scale of single cells, GTA of calcium transients provides quantified measures of connectivity within neural "microcircuits" 32 . Changes at the scale of microcircuits may be important in understanding early disease states, as functional changes of microcircuitry can be detected prior to onset of primary disease associated behavioral deficits 27,28,33 .…”

Three-dimensional in vitro model of the device-tissue interface reveals innate neuroinflammation can be mitigated by antioxidant ceria nanoparticles

“…We used a mathematical method called graph theoretical analysis (GTA) to describe the complex functional interactions within a network 51,52 . Application of GTA to a graph made up of single cell "nodes" is a characterization of network behavior of "microcircuits" 53,54 , which are sensitive to subtle changes in network dynamics that precede gross histological and behavioral deficits in other neuroinflammatory and neurodegenerative disease states [55][56][57][58] . Examination of microcircuit dynamics is particularly well suited to the device-tissue interface, as the neuroinflammatory response is localized to the device and likely does not extend to multiple brain regions at the "mesocircuit" level 59 .…”