The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

Currently, there are no medications that target core deficits of social communication and restrictive, repetitive patterns of behavior in persons with autism spectrum disorders (ASDs). Adults with Down syndrome (DS) display a progressive worsening of adaptive functioning, which is associated with Alzheimer's disease (AD)-like histopathological changes in brain. Similar to persons with ASDs, there are no effective medication strategies to prevent or retard the progressive worsening of adaptive functions in adults with DS. Data suggest that the alpha(7)-subunit containing nicotinic acetylcholine receptor (alpha(7)nAChR) is implicated in the pathophysiology and serves as a promising therapeutic target of these disorders. In DS, production of the amyloidogenic A beta(1-42) peptide is increased and binds to the alpha(7)nAChR or the lipid milieu associated with this receptor, causing a cascade that results in cytotoxicity and deposition of amyloid plaques. Independently of their ability to inhibit the complexing of A beta(1-42) with the alpha(7)nAChR, alpha(7)nAChR agonists and positive allosteric modulators (PAMs) also possess procognitive and neuroprotective effects in relevant in vivo and in vitro models. The procognitive and neuroprotective effects of alpha(7)nAChR agonist interventions may be due, at least in part, to stimulation of the PI31CK/Akt signaling cascade, cross-talk with the Wnt/beta-catenin signaling cascade and both transcriptional and non-transcriptional effects of beta-catenin, and effects of transiently increased intraneuronal concentrations of Ca2+ on metabolism and the membrane potential. Importantly, alpha(7)nAChR PAMs are particularly attractive medication candidates because they lack intrinsic efficacy and act only when and where endogenous acetylcholine is released or choline is generated. (C) 2015 Elsevier Inc. All rights reserved.