The absence of the protein dystrophin causes a muscular dystrophy in mdx mice (the most commonly used murine model of Duchenne muscular dystrophy in humans). Dystrophin is normally expressed in a range of tissues including areas of the CNS (Anderson et al. 2002). In Purkinje cells from normal mice the P-dystrophin isoform is organised in punctate clusters at the postsynaptic densities co-localised with the GABA_A receptor subunit clusters. Kneusel et al. (1999) showed a marked decrease in GABA_A receptor clusters immunoreactive for α1 and α2 subunits in cerebellar Purkinje cells of mdx in which the P-dystrophin isoform is absent.

Experiments were performed on cerebellar slices taken from mdx mice (C57Bl/10 mdx) and age-matched controls (C57Bl/10 ScSn). Mice were anaesthetised with halothane and then killed by cervical dislocation. The cerebellum was rapidly removed, bissected and transferred to ice-cold, carbogenated artificial cerebrospinal fluid (ACSF). Parasagittal slices (250 µm) were cut and transferred to carbogenated ACSF at room temperature. Cerebellar Purkinje cells were identified using IR-DIC optics and X 40 immersion lens. Intracellular recordings were obtained from Purkinje cells using glass micropipettes (~120 MΩ) filled with 2 M potassium acetate. EPSPs were evoked by electrical stimulation using a concentric stimulating electrode positioned in the molecular layer of the cerebellar slice close to the Purkinje cell under study. Where the SD in each group was equal, a Student’s t test was used to statistically compare control and mdx groups, and where there was a significant difference between the S.D. from each group a Mann-Whitney test was used. Data are presented as means ± S.E.M.

The resting membrane potential for our sample of control Purkinje cells had a mean of -64 mV (± 2.7; n = 10) and for mdx cells a mean of -69 mV (± 3.2; n = 11), which did not differ significantly (P = 0.34, n = 21, t test). The mean of the input resistance for control Purkinje cells of 13 MΩ (± 1.7, n = 8) did not differ significantly from the mean for mdx cells of 15 MΩ (± 3.8, n = 7) (P = 0.867, n = 15, Mann-Whitney). The average of the increase in EPSP amplitude in control Purkinje cells on application of bicuculline was 75.8 % (± 23; n = 10) and for mdx cells was 34.8 % (± 9.2; n = 11). Although the difference in the means is not quite statistically significant at the 5 % level (P = 0.057, Mann-Whitney), the data clearly indicate a difference in the extent to which the amplitude of the net evoked EPSP of control cells and mdx cells is affected by the GABA_A receptor antagonist.

Our results provide functional data that are consistent with the histological findings of a reduction in GABA_A channel clusters in Purkinje cells of dystrophic mice.

All procedures accord with current National and local guidelines.