Dysregulation of Neuronal Nicotinic Acetylcholine Receptor-Cholesterol Crosstalk in Autism Spectrum Disorder

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.

Keywords: acetylcholine receptor-cholesterol interactions; autism spectrum disorder; cholesterol; nicotinic receptor (nAChR); perinatal period.

Interconnections between nicotinic and GABAergic neurotransmission, cholesterol, and neurodegenerative disorders, Autism Spectrum Disorder, and other syndromes.

Figure 1

Core symptoms of autism spectrum disorder (ASD). Individuals diagnosticated with ASD present impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, restricted range of interests, and altered sensory processing.

Figure 2

Biosynthetic and catabolic pathways in the brain. Cholesterol is the end product of the mevalonate pathway. Three molecules of acetyl-coenzyme A (acetyl-CoA) are required to generate 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) which is the substrate of HMG-CoA reductase (HMGCR), the mevalonic acid-generating enzyme. This is the only limiting rate reaction in cholesterol synthesis and is the target of statins, the cholesterol-lowering drugs. Mevalonic acid is then converted to farnesyl diphosphate (farnesyl-PP) and squalene. The latter is then converted to 2,3 oxidosqualene by squalene epoxidase (SQLE). Then a series of enzymes catalyzes the synthesis of zymosterol, which can, in turn, be converted to cholesterol via desmosterol by 24-dehydrocholesterol reductase, also known as the Bloch pathway (operating in astrocytes) or via lathosterol (not shown), which is the precursor of 7-dehydrocholesterol, also known as the Kandutsch-Russell pathway (the minority pathway in neurons). The enzyme 7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol to cholesterol, is defective in patients with SLOS. Cholesterol, in turn, must be converted to 24-S-hydroxycholesterol (24-OHC) by 24-hydroxylase (CYP46) to be able to permeate the blood-brain barrier (BBB). Asperger syndrome (Asperger); Smith–Lemli–Opitz syndrome (SLOS); Rett syndrome (RETT); Fragile-X syndrome (FXS); Apolipoprotein E (ApoE); methyl CpG binding protein 2 (Mecp2); low-density lipoproteins (LDL); high-density lipoproteins (HDL). Figure created using Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 3

Postsynaptic neuron regulation via excitatory (glutamatergic/cholinergic) and inhibitory (GABAergic) afferents. Note the presence of nAChRs in the three presynaptic nerve endings as well as in the postsynaptic neuron. Glu can stimulate either NMDA- or AMPA-type glutamatergic receptors, which together with nAChRs, cause depolarization which leads to LTP of the postsynaptic membrane. GABA channel activation results in hyperpolarization of this membrane and favors LTD. Figure created using Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License. Glu, glutamate.

Figure 4

Switch in GABA action from excitatory in the developing mammalian brain to inhibitory in the postnatal brain. The Cl⁻ ion flux is reversed during the neurodevelopmental change, transforming the depolarizing current into a hyperpolarizing signal. Figure created using Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 5

Allopregnanolone synthesis from cholesterol (Chol) in both mature oligodendrocytes (the cells responsible for forming the central myelin) and neurons. Allopregnanolone and other neurosteroids act as transcriptional factors that regulate gene expression upon back-oxidation into 5α-pregnane steroids, and also modulate neuronal excitability by interacting with neurotransmitter receptors. Allopregnanolone in particular is a positive allosteric modulator of the GABA_AR. Preg, pregnenolone; Prog, progesterone; 5α-dihydroprog, 5α-dihydroprogesterone. Figure created using Servier Medical Art Commons Attribution 3.0 Unported License (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.