Molecular analysis of nicotinic receptor expression in autism.
Autism is a developmental disorder of unknown aetiopathology and lacking any specific pharmacological therapeutic intervention. Neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA) and acetylcholine have been implicated. Abnormalities in nicotinic acetylcholine receptors have been identified including cortical loss of binding to the alpha4/beta2 subtype and increase in cerebellar alpha7 binding. Receptor expression (mRNA) has not so far been systematically examined. This study aims to further explore the role of nicotinic receptors in autism by analysing nicotinic receptor subunit mRNA in conjunction with protein levels and receptor binding in different brain areas. Quantitative RT-PCR for alpha4, alpha7 and beta2 subunit mRNA expression levels; alpha3, alpha4, alpha7 and beta2 subunit protein expression immunochemistry and specific radioligand receptor binding were performed in adult autism and control brain samples from cerebral cortex and cerebellum. Alpha4 and beta2 protein expression and receptor binding density as well as alpha4 mRNA levels were lower in parietal cortex in autism, while alpha7 did not change for any of these parameters. In cerebellum, alpha4 mRNA expression was increased, whereas subunit protein and receptor levels were decreased. Alpha7 receptor binding in cerebellum was increased alongside non-significant elevations in mRNA and protein expression levels. No significant changes were found for beta2 in cerebellum. The data obtained, using complementary measures of receptor expression, indicate that reduced gene expression of the alpha4beta2 nicotinic receptor in the cerebral cortex is a major feature of the neurochemical pathology of autism, whilst post-transcriptional abnormalities of both this and the alpha7 subtype are apparent in the cerebellum. The findings point to dendritic and/or synaptic nicotinic receptor abnormalities that may relate to disruptions in cerebral circuitry development.
Martin-Ruiz
C M
CM
Joint MRC/University of Newcastle upon Tyne, Centre Development in Clinical Brain Ageing, Department of Neuropathology, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, UK. c.m.martin-ruiz@ncl.ac.uk
Lee
M
M
Perry
R H
RH
Baumann
M
M
Court
J A
JA
Perry
E K
EK
D000109:Acetylcholine / Q000378:metabolism; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism*; D001667:Binding, Competitive / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010296:Parietal Lobe / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000109:Acetylcholine; D021122:Protein Subunits; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579167:Chrna7 protein, human