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

Abstract

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 α7-subunit containing nicotinic acetylcholine receptor (α7nAChR) is implicated in the pathophysiology and serves as a promising therapeutic target of these disorders. In DS, production of the amyloidogenic Aβ1-42 peptide is increased and binds to the α7nAChR 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 Aβ1-42 with the α7nAChR, α7nAChR 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 α7nAChR agonist interventions may be due, at least in part, to stimulation of the PI3K/Akt signaling cascade, cross-talk with the Wnt/β-catenin signaling cascade and both transcriptional and non-transcriptional effects of β-catenin, and effects of transiently increased intraneuronal concentrations of Ca(2+) on metabolism and the membrane potential. Importantly, α7nAChR 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.

• Authors: Stephen I Deutsch, Jessica A Burket, Maria R Urbano, Andrew D Benson
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 97 Issue 4 Pg. 363-377 (Oct 15 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 26074265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Central Nervous System Agents
• alpha7 Nicotinic Acetylcholine Receptor

Topics

• Autism Spectrum Disorder (drug therapy, genetics, metabolism)
• Central Nervous System Agents (pharmacology)
• Down Syndrome (drug therapy, genetics, metabolism)
• Genetic Predisposition to Disease
• Humans
• alpha7 Nicotinic Acetylcholine Receptor (genetics, metabolism)