Cholinergic Homeostatic Synaptic Plasticity Drives the Progression of Aβ-Induced Changes in Neural Activity

• Published in: Cell reports (Cambridge) 2018-07, Vol.24 (2), p.342-354
• Main Authors: Hahm, Eu-Teum, Nagaraja, Raghavendra Y., Waro, Girma, Tsunoda, Susan
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; beta-amyloid; Drosophila; homeostatic synaptic plasticity; α7 nAChR
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.06.029

Homeostatic synaptic plasticity (HSP) is the ability of neurons to exert compensatory changes in response to altered neural activity. How pathologically induced activity changes are intertwined with HSP mechanisms is unclear. We show that, in cholinergic neurons from Drosophila, beta-amyloid (Aβ) peptides Aβ40 and Aβ42 both induce an increase in spontaneous activity. In a transgenic line expressing Aβ42, we observe that this early increase in spontaneous activity is followed by a dramatic reduction in spontaneous events, a progression that has been suggested to occur in cholinergic brain regions of mammalian models of Alzheimer’s disease. We present evidence that the early enhancement in synaptic activity is mediated by the Drosophila α7 nicotinic acetylcholine receptor (nAChR) and that, later, Aβ42-induced inhibition of synaptic events is a consequence of Dα7-dependent HSP mechanisms induced by earlier hyperactivity. Thus, while HSP may initially be an adaptive response, it may also drive maladaptive changes and downstream pathologies. [Display omitted] •Aβ42 induces an increase in cholinergic activity followed by synaptic inhibition•α7 nAChRs mediate Aβ42-induced hyperactivity•Acutely induced hyperactivity in wild-type results in later synaptic inhibition•Blocking early Aβ42-induced hyperactivity prevents later synaptic silencing In models of Alzheimer’s disease, Aβ peptides have been shown to induce both increases and decreases in neural activity. Hahm et al. present evidence that an early Aβ-induced enhancement in cholinergic activity, mediated by the α7 nAChR, triggers endogenous homeostatic plasticity mechanisms that result in downstream synaptic silencing.