Nicotinic Acetylcholine Receptors in Autism Spectrum Disorders: Therapeutic Implications

Abstract

A shared pathophysiological abnormality in autism spectrum disorders (ASDs) may be diminished central inhibitory tone, which disrupts a delicate balance between excitation and inhibition. Cholinergic projections from the basal forebrain and other areas provide modulatory influences on central inhibitory tone, and efficient transduction of the acetylcholine (ACh) signal is necessary for maintenance of the balance between excitation and inhibition. This chapter reviews evidence for abnormalities of cholinergic neurotransmission in ASDs and develops the pharmacological rationale for selectively targeting nicotinic acetylcholine receptors (nAChR), especially those containing α7 subunits, as a possible therapeutic intervention. The development of positive allosteric modulators (PAMs) of nAChR makes this a particularly attractive approach as PAMs lack intrinsic activity and are only active where and when ACh is released in the brain to increase the magnitude of its effect. Additionally, specific PAMs may oppose agonist-induced desensitization, which lend themselves to therapies in which they are combined with agonists; combination strategies may have special value when there is diminished density of functional receptors. Also, there are endogenous modulators of cholinergic neurotransmission (e.g., kynurenic acid), whose levels may be modulated to achieve therapeutic goals.