Nicotinic receptor abnormalities in the cerebellar cortex in
autism.
Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, Iversen P, Bauman
M, Perry E.
MRC/University of Newcastle Upon Tyne Development in Clinical Brain Ageing,
Newcastle upon Tyne, UK.
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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