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This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 577/1/127    most recent jphysiol.2006.112482v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harvey, V. L. Articles by Stephens, G. J. Search for Related Content PubMed PubMed Citation Articles by Harvey, V. L. Articles by Stephens, G. J. Related Collections Neuroscience

¹ School of Pharmacy, University of Reading, Whiteknights, PO Box 228, Reading RG6 6AJ, UK
² Department of Pharmacology
³ Wolfson Institute for Biomedical Research and Department of Physiology, University College London, Gower Street, London WC1E 6BT, UK

Ionotropic -amino butyric acid (GABA) receptors composed of heterogeneous molecular subunits are major mediators of inhibitory responses in the adult CNS. Here, we describe a novel ionotropic GABA receptor in mouse cerebellar Purkinje cells (PCs) using agents reported to have increased affinity for subunit-containing GABA_C over other GABA receptors. Exogenous application of the GABA_C-preferring agonist cis-4-aminocrotonic acid (CACA) evoked whole-cell currents in PCs, whilst equimolar concentrations of GABA evoked larger currents. CACA-evoked currents had a greater sensitivity to the selective GABA_C antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) than GABA-evoked currents. Focal application of agonists produced a differential response profile; CACA-evoked currents displayed a much more pronounced attenuation with increasing distance from the PC soma, displayed a slower time-to-peak and exhibited less desensitization than GABA-evoked currents. However, CACA-evoked currents were also completely blocked by bicuculline, a selective agent for GABA_A receptors. Thus, we describe a population of ionotropic GABA receptors with a mixed GABA_A/GABA_C pharmacology. TPMPA reduced inhibitory synaptic transmission at interneurone–Purkinje cell (IN–PC) synapses, causing clear reductions in miniature inhibitory postsynaptic current (mIPSC) amplitude and frequency. Combined application of NO-711 (a selective GABA transporter subtype 1 (GAT-1) antagonist) and SNAP-5114 (a GAT-(2)/3/4 antagonist) induced a tonic GABA conductance in PCs; however, TPMPA had no effect on this current. Immunohistochemical studies suggest that subunits are expressed predominantly in PC soma and proximal dendritic compartments with a lower level of expression in more distal dendrites; this selective immunoreactivity contrasted with a more uniform distribution of GABA_A 1 subunits in PCs. Finally, co-immunoprecipitation studies suggest that subunits can form complexes with GABA_A receptor 1 subunits in the cerebellar cortex. Overall, these data suggest that subunits contribute to functional ionotropic receptors that mediate a component of phasic inhibitory GABAergic transmission at IN–PC synapses in the cerebellum.

(Received 29 April 2006; accepted after revision 24 August 2006; first published online 31 August 2006)
Corresponding author G. J. Stephens: School of Pharmacy, University of Reading, Whiteknights, PO Box 228, Reading RG6 6AJ, UK. Email: g.j.stephens{at}reading.ac.uk