Circuit Mechanisms of Neurodegenerative Diseases

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) or Amyotrophic lateral sclerosis (ALS), are histopathologically characterized by the formation of protein aggregates and the selective death of a defined population of neurons. These diseases have traditionally been viewed as being caused by the selective dysfunction of those vulnerable neurons via cell-autonomous mechanisms. Current evidence, however, strongly implicates a causal involvement of altered neuronal circuit function in triggering and perpetuating the degenerative cascade. Recent methodological advances offered by newly developed genetic tools, in vivo electrophysiology and imaging techniques, have enabled the selective assessment and manipulation of dedicated cell populations and neural circuits in vivo. Such approaches have provided evidence that circuit alterations result from complex changes at the level of synapses, intrinsic excitability of cells and disrupted connectivity within local microcircuits and between long-range projection areas, ultimately giving rise to altered activity patterns of neurons, impaired information processing in a disease-stage dependent manner and eventual neuronal loss. Intriguingly, preclinical studies in rodent models suggest that many of those structural and functional alterations within a neuronal network are already found at early presymptomatic stages, long before typical markers of degeneration are detectable. These findings support the notion that circuit dysfunction is likely not only a consequence of degenerative processes in NDs, but can in fact represent the main driver of the pathology. This novel concept not only opens up new therapeutic avenues by shedding light into brain-region, cell-type specific alterations occurring in a disease-stage specific manner, but moreover, it has the potential to identify novel diagnostic approaches, too.

With this Research Topic, we aim at providing compelling recent evidence in support of this hypothesis covering various NDs. This collection may contain original research articles as well as reviews providing an overview of the current knowledge and technological advances in the mentioned area of neurodegeneration.