The early stages of Alzheimer's disease (AD) have been linked to microcircuit dysfunction and pathophysiological neuronal firing in several brain regions. Inhibitory GABAergic microcircuitry is a critical feature of stable neural-circuit function in the healthy brain, and its dysregulation has therefore been proposed as contributing to AD-related pathophysiology. However, exactly how the critical balance between excitatory and inhibitory microcircuitry is modified by AD pathogenesis remains unclear. Here, we set the current evidence implicating dysfunctional GABAergic microcircuitry as a driver of early AD pathophysiology in a simple conceptual framework. Our framework is based on a generalised reductionist model of firing-rate control by local feedback inhibition. We use this framework to consider multiple loci that may be vulnerable to disruption by AD pathogenesis. We first start with evidence investigating how AD-related processes may impact the gross number of inhibitory neurons in the network. We then move to discuss how pathology may impact intrinsic cellular properties and firing thresholds of GABAergic neurons. Finally, we cover how AD-related pathogenesis may disrupt synaptic connectivity between excitatory and inhibitory neurons. We use the feedback inhibition framework to discuss and organise the available evidence from both preclinical rodent work and human studies in AD patients and conclude by identifying key questions and understudied areas for future investigation.
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| http://dx.doi.org/10.1016/j.semcdb.2022.06.017 | DOI Listing |
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