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Incremental conductance levels of GABA_A receptors in dopaminergic neurones of the rat substantia nigra pars compacta

A. Guyon, S. Laurent, D. Paupardin-Tritsch, J. Rossier * and D. Eugène

Molecular and biophysical properties of GABA_A receptors of dopaminergic (DA) neurones of the pars compacta of the rat substantia nigra were studied in slices and after acute dissociation.

Single-cell reverse transcriptase-multiplex polymerase chain reaction confirmed that DA neurones contained mRNAs encoding for the 3 subunit of the GABA_A receptor, but further showed the presence of 4 subunit mRNAs. 2, 1 and 1 subunit mRNAs were never detected. Overall, DA neurones present a pattern of expression of GABA_A receptor subunit mRNAs containing mainly 3/42/33.

Outside-out patches were excised from DA neurones and GABA_A single-channel patch-clamp currents were recorded under low doses (1-5 µM) of GABA or isoguvacine, a selective GABA_A agonist. Recordings presented several conductance levels which appeared to be integer multiples of an elementary conductance of 4-5 pS. This property was shared by GABA_A receptors of cerebellar Purkinje neurones recorded in slices (however, with an elementary conductance of 3 pS). Only the 5-6 lowest levels were analysed.

A progressive change in the distribution of occupancy of these levels was observed when increasing the isoguvacine concentration (up to 10 µM) as well as when adding zolpidem (20-200 nM), a drug acting at the benzodiazepine binding site: both treatments enlarged the occupancy of the highest conductance levels, while decreasing that of the smallest ones. Conversely, Zn²⁺ (10 µM), a negative allosteric modulator of GABA_A receptor channels, decreased the occupancy of the highest levels in favour of the lowest ones.

These properties of 3/42/33-containing GABA_A receptors would support the hypothesis of either single GABA_A receptor channels with multiple open states or that of a synchronous recruitment of GABA_A receptor channels that could involve their clustering in the membranes of DA neurones.