An Evolving Therapeutic Rationale for Targeting the α₇ Nicotinic Acetylcholine Receptor in Autism Spectrum Disorder

Abnormalities of cholinergic nuclei, cholinergic projections, and cholinergic receptors, as well as abnormalities of growth factors involved in the maturation and maintenance of cholinergic neurons, have been described in postmortem brains of persons with autism spectrum disorder (ASD). Further, microdeletions of the 15q13.3 locus that encompasses CHRNA7, the gene coding the α₇ nicotinic acetylcholine receptor (α₇ nAChR), are associated with a spectrum of neurodevelopmental disorders, including ASD. The heterozygous 15q13.3 microdeletion syndrome suggests that diminished or impaired transduction of the acetylcholine (ACh) signal by the α₇ nAChR can be a pathogenic mechanism of ASD. The α₇ nAChR has a role in regulating the firing and function of parvalbumin (PV)-expressing GABAergic projections, which synchronize the oscillatory output of assemblies of pyramidal neurons onto which they project. Synchronous oscillatory output is an electrophysiological substrate for higher executive functions, such as working memory, and functional connectivity between discrete anatomic areas of the brain. The α₇ nAChR regulates PV expression and works cooperatively with the co-expressed NMDA receptor in subpopulations of GABAergic interneurons in mouse models of ASD. An evolving literature supports therapeutic exploration of selectively targeted cholinergic interventions for the treatment of ASD, especially compounds that target the α₇ nAChR subtype. Importantly, development and availability of high-affinity, brain-penetrable, α₇ nAChR-selective agonists, partial agonists, allosteric agonists, and positive allosteric modulators (PAMs) should facilitate "proof-of-principle/concept" clinical trials. nAChRs are pentameric allosteric proteins that function as ligand-gated ion channel receptors constructed from five constituent polypeptide subunits, all of which share a common structural motif. Importantly, in addition to α₇ nAChR-gated Ca²⁺ conductance causing membrane depolarization, there are emerging data consistent with possible metabotropic functions of this ionotropic receptor. The ability of α₇-selective type II PAMs to "destabilize" the desensitized state and promote ion channel opening may afford them therapeutic advantages over orthosteric agonists. The current chapter reviews historic and recent literature supporting selective therapeutic targeting of the α₇ nAChR in persons affected with ASD.