Cholinergic Synaptic Homeostasis

About This Grant

Project Summary Homeostatic Synaptic Plasticity (HSP) is the ability of neurons to exert compensatory changes in synaptic strength in response to altered neural activity, thereby acting as a critical protective mechanism during physiological processes such as learning/memory and development, as well as pathological conditions. Although nearly all HSP studies have focused on glutamatergic synapses, there is substantial evidence that cholinergic regions of the brain also experience significant changes in neural activity in multiple disorders and diseases, including Alzheimer’s disease (AD). Nevertheless, cholinergic HSP, especially at central synapses, and the mechanisms that regulate it have remained remarkably understudied. In the proposed studies, we will use the primarily cholinergic CNS of Drosophila as a genetically tractable model in which to unravel the molecular mechanisms underlying and regulating cholinergic HSP. This is currently the only model that has been developed to study central cholinergic HSP. In the proposed studies, we will validate cholinergic HSP in neurons in their intact circuitry for the first time. We will also use this model to address outstanding questions about the mechanisms that underlie and regulate HSP. We will dissect the role of the ER protein NACHO in the inactivity- induced up-regulation of the Drosophila α7 nAChR that underlies HSP. We will also examine in vivo the role of the transcription factors, NFAT and CREB, in regulating HSP, and identify downstream ion channel gene targets that contribute to HSP. Since ion channel/receptor genes and cellular regulatory mechanisms have proven to be highly conserved across species, we expect our findings to inform our understanding of cholinergic HSP in mammalian systems, and have broader, potentially, therapeutic, value.