Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, C90
Electrophysiological deficits at GABAergic synapses on Purkinje cells of the dystrophin-deficient mdx mouse: possible implications for Duchenne Muscular Dystrophy
S. I. Head1, J. W. Morley2, S. L. Kueh2, J. Dempster3
1. Physiology, University of New South Wales, Sydney, New South Wales, Australia. 2. Anatomy, University of Western Sydney, Sydney, New South Wales, Australia. 3. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
Duchenne muscular dystrophy (DMD) results from an absence of the protein dystrophin. It is characterized by severe wasting of skeletal muscle. There is also a significant, but often overlooked, accompanying cognitive and behavioural deficit(1). In the cerebellum dystrophin is normally localized at the postsynaptic membrane of GABAergic synapses on Purkinje cells. Here, we investigate the effect of an absence of dystrophin on the number of functional GABAA channels located at the synapse in cerebellar Purkinje cells of the dystrophin-deficient mdx mouse. Whole-cell patch-clamp recordings of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were performed in cerebellar slices from mdx and littermate control mice. Using non-stationary noise analysis, we found a significant difference in the number of receptors at GABAergic synapses in mdx mice (38.38 ± 2.95; n=14) compared to littermate controls (53.03 ± 4.11; n=12) (p = 0.01). In response to the application of the GABA agonist gaboxadol we found a significant difference in the gaboxadol induced change in holding current in mdx mice (65.01 ± 5.89 pA; n=9) compared to littermate controls (37.36 ± 3.82 pA; n=8). These results suggest that in cerebellar Purkinje cells of dystrophin-deficient mdx mice there is a reduction in the number of receptors localised at GABAergic synapses, and an accompanying increase in extrasynaptic GABAA receptors, indicating that dystrophin plays an important role in ion channel localization and stabilization at the post-synaptic membrane. If similar changes occur in the CNS in boys with DMD, it may impact on the function of neural networks and contribute to motor, behavioural and cognitive impairment apparent in many boys with DMD.
Where applicable, experiments conform with Society ethical requirements