Research ReportQuantitative changes of nicotinic receptors in the hippocampus of dystrophin-deficient mice

Lack of dystrophin in Duchenne muscle dystrophy (DMD) and in the mutant mdx mouse results in progressive muscle degeneration, structural changes at the neuromuscular junction, and destabilization of the nicotinic acetylcholine receptors (nAChRs). One-third of DMD patients also present non-progressive cognitive impairments. Considering the role of the cholinergic system in cognitive functions, the number of nAChR binding sites and the mRNA levels of α4, β2, and α7 subunits were determined in brain regions normally enriched in dystrophin (cortex, hippocampus and cerebellum) of mdx mice using specific ligands and reverse-transcription polymerase chain reaction assays, respectively. Membrane preparations of these brain regions were obtained from male control and mdx mice at 4 and 12 months of age. The number of [3H]-cytisine (α4β2) and [125I]-α-bungarotoxin ([125I]-αBGT, α7) binding sites in the cortex and cerebellum was not altered with age or among age-matched control and mdx mice. A significant reduction in [3H]-cytisine (48%) and [125I]-αBGT (37%) binding sites was detected in the hippocampus of mdx mice at 12 months of age. When compared with the age-matched control groups, the mdx mice did not have significantly altered [3H]-cytisine binding in the hippocampus, but [125I]-αBGT binding in the same brain region was 52% higher at 4 months and 20% lower at 12 months. mRNA transcripts for the nAChR α4, β2, and α7 subunits were not significantly altered in the same brain regions of all animal groups. These results suggest a potential alteration of the nicotinic cholinergic function in the hippocampus of dystrophin-deficient mice, which might contribute to the impairments in cognitive functions, such as learning and memory, that have been reported in the dystrophic murine model and DMD patients.

► Dystrophin loss in mdx mice destabilizes the nAChR at the neuromuscular junction. ► We quantified the binding sites for α4β2 and α7 nAChRs in the brain of mdx mice. ► α7 nAChR-binding sites were increased in the hippocampus of 4-month-old mdx mice. ► α4β2 and α7 nAChRs binding sites were decreased in the hippocampus of 12-month-old mdx mice. ► The dysfunction of central nicotinic synapses may be associated with dystrophin loss.