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Cited by 232Nicotinic Acetylcholine Receptors StudyAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Nicotinic receptor abnormalities in the cerebellar cortex in autism

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Lee, M.·2002·Brain
DOI 10.1093/brain/awf160
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Abstract

Autism is a common developmental disorder associated with structural and inferred neurochemical abnormalities of the brain. Cerebellar abnormalities frequently have been identified, based on neuroimaging or neuropathology. Recently, the cholinergic neurotransmitter system has been implicated on the basis of nicotinic receptor loss in the cerebral cortex. Cerebellar cholinergic activities were therefore investigated in autopsy tissue from a series of autistic individuals. The presynaptic cholinergic enzyme, choline acetyltransferase, together with nicotinic and muscarinic receptor subtypes were compared in the cerebellum from age-matched mentally retarded autistic (eight), normal control (10) and non-autistic mentally retarded individuals (11). The nicotinic receptor binding the agonist epibatidine (the high affinity receptor subtype, consisting primarily of alpha3 and alpha4, together with beta2 receptor subunits) was significantly reduced by 40-50% in the granule cell, Purkinje and molecular layers in the autistic compared with the normal group (P < 0.05). There was an opposite increase (3-fold) in the nicotinic receptor binding alpha-bungarotoxin (to the alpha7 subunit) which reached significance in the granule cell layer (P < 0.05). These receptor changes were paralleled by a significant reduction (P < 0.05) and non-significant increase, respectively, of alpha4 and alpha7 receptor subunit immunoreactivity measured using western blotting. Immunohistochemically loss of alpha(4 )reactivity was apparent from Purkinje and the other cell layers, with increased alpha7 reactivity in the granule cell layer. There were no significant changes in choline acetyltransferase activity, or in muscarinic M1 and M2 receptor subtypes in autism. In the non-autistic mentally retarded group, the only significant abnormality was a reduction in epibatidine binding in the granule cell and Purkinje layers. In two autistic cases examined histologically, Purkinje cell loss was observed in multiple lobules throughout the vermis and hemispheres. This was more severe in one case with epilepsy, which also showed vermis folial malformation. The case with less severe Purkinje cell loss also showed cerebellar white matter thinning and demyelination. These findings indicate a loss of the cerebellar nicotinic alpha4 receptor subunit in autism which may relate to the loss of Purkinje cells, and a compensatory increase in the alpha7 subunit. It remains to be determined how these receptor abnormalities are involved in neurodevelopment in autism and what is the relationship to mental function. Since nicotinic receptor agonists enhance attentional function and also induce an elevation in the high affinity receptor, nicotinic therapy in autism may be worth considering.

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Crossref · 10.1093/brain/awf160

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  • Post-mortem autism cases show 40-50% reduced nicotinic cholinergic receptor types α3, α4, and β2 in granule cell, Purkinje cell, and molecular layers of cerebellum relative to matched controls.

    “Key findings of 40–50% reduced nicotinic cholinergic receptor type α3, α4, and β2 measured by the high affinity agonist epibatidine in post-mortem autism cases relative to matched controls was reported in the granule cell, Purkinje cell and molecular layers in the cerebellum [172].”

    From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [172]

  • No changes in muscarinic M1 or M2 receptors were found in the cerebellum.

    “Interestingly, no changes in muscarinic M1 or M2 type receptors were found in the cerebellum [172]”

    From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [172]

  • A three-fold increase in nicotinic cholinergic receptor type α7 is found in the granule cell layer of autism cases.

    “In contrast, a three-fold increase in nicotinic cholinergic receptor type α7 measured by receptor binding using α-bungarotoxin was found in the granule cell layer.”

    From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [172]

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Authors
Lee, M.
Affiliations
Newcastle University (GB)
Corresponding author
Lee, M.
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2002-07-01
Volume
125
Issue
7
Pages
1483-1495
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awf160
OpenAlex
W2119098759
Cited by
232
References
79
Citations by year
2026: 4 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 4 · 2021: 10 · 2020: 7 · 2019: 4 · 2018: 10 · 2017: 7 · 2016: 6 · 2015: 11 · 2014: 16 · 2013: 13 · 2012: 13
FWCI
4.29
Type
journal article
Language
en
Open access
Locations
  • Brain (publishedVersion)
  • PubMed (publishedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Autism Research Foundation
  • University of Miami
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
autism spectrum disorder, nicotinic acetylcholine receptors, cerebellum, Purkinje cells, epibatidine binding, alpha-bungarotoxin binding, choline acetyltransferase, muscarinic receptors, cerebellar granule cells
MeSH terms
Adult, Autistic Disorder, Autoradiography, Binding, Competitive, Bungarotoxins, Cerebellar Cortex, Choline O-Acetyltransferase, Down Syndrome, Female, Humans, Immunohistochemistry, Ligands, Male, Intellectual Disability, Purkinje Cells, Pyridines, Receptors, Nicotinic, Bridged Bicyclo Compounds, Heterocyclic, alpha7 Nicotinic Acetylcholine Receptor

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