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The Journal of Neuroscience, May 3, 2006, 26(18):4880-4890; doi:10.1523/JNEUROSCI.3991-05.2006

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Development/Plasticity/Repair
Distinct Physiological Mechanisms Underlie Altered Glycinergic Synaptic Transmission in the Murine Mutants spastic, spasmodic, and oscillator

Brett A. Graham,¹ Peter R. Schofield,^2,3,4 Pankaj Sah,⁵ Troy W. Margrie,⁶ and Robert J. Callister¹

¹School of Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, Callaghan, New South Wales 2308, Australia, ²Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia, ³University of New South Wales, Sydney, New South Wales 2052, Australia, ⁴Prince of Wales Medical Research Institute, Randwick, New South Wales 2031, Australia, ⁵Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia, and ⁶Department of Physiology, University College London, London WC1E 6JJ, United Kingdom

Correspondence should be addressed to Dr. Robert J. Callister, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Callaghan, New South Wales 2308, Australia. Email: robert.callister{at}newcastle.edu.au

Spastic (spa), spasmodic (spd), and oscillator (ot) mice have naturally occurring glycine receptor (GlyR) mutations, which manifest as motor deficits and an exaggerated "startle response." Using whole-cell recording in hypoglossal motoneurons, we compared the physiological mechanisms by which each mutation alters GlyR function. Mean glycinergic miniature IPSC (mIPSC) amplitude and frequency were dramatically reduced (>50%) compared with controls for each mutant. mIPSC decay times were unchanged in spa/spa (4.5 ± 0.3 vs 4.7 ± 0.2 ms), reduced in spd/spd (2.7 ± 0.2 vs 4.7 ± 0.2 ms), and increased in ot/ot (12.3 ± 1.2 vs 4.8 ± 0.2 ms). Thus, in spastic, GlyRs are functionally normal but reduced in number, whereas in spasmodic, GlyR kinetics is faster. The oscillator mutation results in complete absence of 1-containing GlyRs; however, some non-1-containing GlyRs persist at synapses. Fluctuation analysis of membrane current, induced by glycine application to outside-out patches, showed that mean single-channel conductance was increased in spa/spa (64.2 ± 4.9 vs 36.1 ± 1.4 pS), but unchanged in spd/spd (32.4 ± 2.1 vs 35.3 ± 2.1 pS). GlyR-mediated whole-cell currents in spa/spa exhibited increased picrotoxin sensitivity (27 vs 71% block for 100 µM), indicating 1 homomeric GlyR expression. The picrotoxin sensitivity of evoked glycinergic IPSCs and conductance of synaptic GlyRs, as determined by nonstationary variance analysis, were identical for spa/spa and controls. Together, these findings show the three mutations disrupt GlyR-mediated inhibition via different physiological mechanisms, and the spastic mutation results in "compensatory" 1 homomeric GlyRs at extrasynaptic loci.

Key words: hypoglossal motoneuron; glycine receptor; mouse; inhibition; ion channel; brainstem

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Received Sept. 20, 2005; revised Feb. 21, 2006; accepted March 14, 2006.

Correspondence should be addressed to Dr. Robert J. Callister, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Callaghan, New South Wales 2308, Australia. Email: robert.callister{at}newcastle.edu.au

This article has been cited by other articles:

				B. A. Graham, A. M. Brichta, P. R. Schofield, and R. J. Callister Altered potassium channel function in the superficial dorsal horn of the spastic mouse J. Physiol., October 1, 2007; 584(1): 121 - 136. [Abstract] [Full Text] [PDF]

				J. H. Steinbach A slip 'twixt the cup and the lip: a new way to impair function of transmitter-gated channels J. Physiol., May 15, 2007; 581(1): 3 - 3. [Full Text] [PDF]

				A. J. R. Plested, P. J. Groot-Kormelink, D. Colquhoun, and L. G. Sivilotti Single-channel study of the spasmodic mutation {alpha}1A52S in recombinant rat glycine receptors J. Physiol., May 15, 2007; 581(1): 51 - 73. [Abstract] [Full Text] [PDF]

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