ALTERED ACETYLCHOLINE RELEASE IN THE HIPPOCAMPUS OF DYSTROPHIN-DEFICIENT MICE

作者：Parames S F; Coletta Yudice E D; Nogueira F M; De Sousa M B Nering; Hayashi M A; Lima Landman M T R; Lapa A J; Souccar C^*

来源：Neuroscience, 2014, 269: 173-183.

DOI：10.1016/j.neuroscience.2014.03.050

• [H-3]-ACh release
• nicotinic acetylcholine receptor
• vesicular ACh transporter
• hippocampus
• dystrophin
• mdx mouse

Mild cognitive impairments have been described in one-third of patients with Duchenne muscle dystrophy (DMD). DMD is characterized by progressive and irreversible muscle degeneration caused by mutations in the dystrophin gene and lack of the protein expression. Previously, we have reported altered concentrations of alpha 7- and beta 2-containing nicotinic acetylcholine receptors (nAChRs) in hippocampal membranes of dystrophic (mdx) mice. This suggests that alterations in the central cholinergic synapses are associated with dystrophin deficiency. In this study, we examined the release of acetylcholine (ACh) and the level of the vesicular ACh transporter (VAChT) using synaptosomes isolated from brain regions that normally have a high density of dystrophin (cortex, hippocampus and cerebellum), in control and mdx mice at 4 and 12 months of age. ACh release evoked by nicotinic stimulation or K+ depolarization was measured as the tritium outflow from superfused synaptosomes preloaded with [H-3]-choline. The results showed that the evoked tritium release was Ca2+-dependent and mostly formed by [H-3]-ACh. beta 2-containing nAChRs were involved in agonist-evoked [H-3]-ACh release in control and mdx preparations. In hippocampal synaptosomes from 12-month-old mdx mice, nAChR-evoked [H-3]-ACh release increased by 57% compared to age-matched controls. Moreover, there was a 98% increase in [H-3]-ACh release compared to 4-month-old mdx mice. [H-3]-ACh release evoked by K (+) depolarization was not altered, while the VAChT protein level was decreased (19%) compared to that of age- matched controls. In cortical and cerebellar preparations, there was no difference in nAChR-evoked [H-3]-ACh release and VAChT levels between mdx and age-matched control groups. Our previous findings and the presynaptic alterations observed in the hippocampi of 12-month-old mdx mice indicate possible dysfunction of nicotinic cholinergic synapses associated with dystrophin deficiency. These changes may contribute to the cognitive and behavioral abnormalities described in dystrophic mice and patients with DMD.

• 出版日期2014-6-6