Cholinergic Abnormalities in Autism

Abstract

The core dysfunctions of autism spectrum disorders, which include autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified, include deficits in socialization and communication and a need for the preservation of "sameness;" intellectual impairment and epilepsy are common comorbidities. Data suggest that pathological involvement of cholinergic nuclei and altered expression of acetylcholine receptors, particularly nicotinic acetylcholine receptors, occur in brain of persons with autistic disorder. However, many of these studies involved postmortem tissue from small samples of primarily adult persons. Thus, the findings may reflect compensatory changes and may relate more closely to intellectual impairment and the confounding effects of seizures and medications, as opposed to the core dysfunctions of autism. Nonetheless, because of the roles played by acetylcholine receptors in general, and nicotinic acetylcholine receptors in particular, in normal processes of attention, cognition, and memory, selective cholinergic interventions should be explored for possible therapeutic effects. Additionally, there are electrophysiological data that complement the clinical observations of frequent comorbid seizure disorders in these patients, suggesting a disturbance in the balance of excitatory and inhibitory tone in the brains of persons with autistic disorders. Conceivably, because the alpha7 nicotinic acetylcholine receptor is located on the surface of gamma-aminobutyric acid inhibitory neurons, selective stimulation of this receptor would promote gamma-aminobutyric acid's release and restore diminished inhibitory tone. The development of agonists and partial agonists for nicotinic acetylcholine receptors and positive allosteric modulators that enhance the efficiency of coupling between the binding of agonist and channel opening should facilitate consideration of clinical trials.

Neurobiology of rodent self-grooming and its value for translational neuroscience

“…However, increased self-grooming in these animals can be corrected pharmacologically. For example, cholinergic agents (which may be useful in correcting postulated cholinergic deficits in ASD 97,98 and/or some of its clinical symptoms 99 ) reduce self-grooming 19 and other ASD-like behaviours 100 in BTBR mice. Furthermore, repetitive self-grooming behaviour in BTBR mice is rescued by the inhibition of glutamatergic metabotropic mGluR5 receptors 90,101 and by the stimulation of NMDA receptors by d -cycloserine 102 (which has also been shown to ameliorate some behavioural deficits in individuals with ASD 103,104 ).…”

An aberrant precision account of autism

“…In autism, reports of basal forebrain neuron pathology (Kemper and Bauman, 1998), morphological abnormalities (Riva et al, 2011) and reduced cortical cholinergic receptor function (Perry et al, 2001) are consistent with the idea of aberrant cholinergic encoding of precision in autism, and selective cholinergic interventions are considered a fruitful avenue for development of autism therapeutics (Deutsch et al, 2010). In another recent mouse model of autism, systematically increasing the availability of acetylcholine was found to alleviate behavioral symptoms consistent with autism (Karvat and Kimchi, 2013).…”

Nicotinic ACh receptors as therapeutic targets in CNS disorders

“…The reduced gene expression of the α4 and β2 receptor subunits in the cerebral cortex is a major feature of the neurochemical pathology of ASD [120]. If there is a loss of cholinergic tone in the autistic brain, then nAChR ligands that restore or improve cholinergic transmission may be used to compensate for such loss [121, 122]. Therefore agonists and PAMs for α4β2 * nAChRs may be employed to compensate for the loss of nAChR function in the autistic brain.…”