Abstract
Autism spectrum disorder (ASD) is a set of complex neurodevelopmental diseases that include impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, restricted range of interests, and altered sensory processing. The underlying causes of the core symptoms remain unclear, as are the factors that trigger their onset. Given the complexity and heterogeneity of the clinical phenotypes, a constellation of genetic, epigenetic, environmental, and immunological factors may be involved. The lack of appropriate biomarkers for the evaluation of neurodevelopmental disorders makes it difficult to assess the contribution of early alterations in neurochemical processes and neuroanatomical and neurodevelopmental factors to ASD. Abnormalities in the cholinergic system in various regions of the brain and cerebellum are observed in ASD, and recently altered cholesterol metabolism has been implicated at the initial stages of the disease. Given the multiple effects of the neutral lipid cholesterol on the paradigm rapid ligand-gated ion channel, the nicotinic acetylcholine receptor, we explore in this review the possibility that the dysregulation of nicotinic receptor-cholesterol crosstalk plays a role in some of the neurological alterations observed in ASD.
Highlights
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder manifested in childhood by deficits or atypicalities in both social behavior and cognitive function (Lai et al, 2014; Bonnet-Brilhault, 2017; Lord et al, 2018; Figure 1)
Since nAChR function is influenced by its lipid microenvironment and cell-surface trafficking of nAChRs is dependent on cholesterol metabolism (Pediconi et al, 2004; Borroni et al, 2020) we explore in this review the various neurological alterations described in ASD and their possible association with an abnormal crosstalk between nAChRs and cholesterol
The importance of this lipid in the central nervous system (CNS) is two-fold: (1) neurons require the sterol for normal functioning; and (2) cholesterol is an essential constituent of myelin sheaths formed by oligodendrocytes to insulate axons and plasma membranes of astrocytes and neurons (Fracassi et al, 2019)
Summary
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder manifested in childhood by deficits or atypicalities in both social behavior and cognitive function (Lai et al, 2014; Bonnet-Brilhault, 2017; Lord et al, 2018; Figure 1). Changes in social behavior or other subtle incipient autistic features may be noticed even during the first few months of life (Lord, 1995) These observations suggest that there are neuroanatomical and/or neurochemical alterations taking place early in the development of the central nervous system (CNS), and that such departure from normality is at the very root of the pathophysiology of the disorder. Cholesterol concentration alters the physical properties of the bulk membrane and promotes the formation of liquid-ordered (Lo) domains (van Meer et al, 2008) These domains display unique biophysical properties: they have a highly dynamic transient nature and differ structurally from the rest of the bulk lipid bilayer owing to their higher concentration in rigid, saturated acyl chains, cholesterol, and sphingolipids (Borroni et al, 2016), making these Lo domains thicker than the rest of the membrane. Since nAChR function is influenced by its lipid microenvironment (see reviews in Barrantes, 2004, 2017) and cell-surface trafficking of nAChRs is dependent on cholesterol metabolism (Pediconi et al, 2004; Borroni et al, 2020) we explore in this review the various neurological alterations described in ASD and their possible association with an abnormal crosstalk between nAChRs and cholesterol
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