Single-channel properties of synaptic and extrasynaptic GABA(A) receptors suggest differential targeting of receptor subtypes

Many neurons express a multiplicity of GABA(A) receptor subunit isoforms. D espite having only a single source of inhibitory input, the cerebellar gran ule cell displays, at various stages of development, more than 10 different GABA(A) subunit types. This subunit diversity would be expected to result in significant receptor heterogeneity, yet the functional consequences of s uch heterogeneity remain poorly understood. Here we have used single-channe l properties to characterize GABA(A) receptor types in the synaptic and ext rasynaptic membrane of granule cells. In the presence of high concentration s of GABA, which induced receptor desensitization, extrasynaptic receptors in outside-out patches from the soma entered long-lived closed states inter rupted by infrequent clusters of openings. Each cluster of openings, which is assumed to result from the repeated activation of a single channel, was to one of three main conductance states (28, 17, or 12 pS), the relative fr equency of which differed between patches. Such behavior indicates the pres ence of at least three different receptor types. This heterogeneity was not replicated by individual recombinant receptors (alpha(1)beta(2)gamma(2S) o r alpha(1)beta(3)gamma(2S)), which gave rise to clusters of a single type o nly. By contrast, the conductance of synaptic receptors, determined by fluc tuation analysis of the synaptic current or direct resolution of channel ev ents, was remarkably uniform and similar to the highest conductance value s een in extrasynaptic patches. These results suggest that granule cells expr ess multiple GABA(A) receptor types, but only those with a high conductance , most likely containing a gamma subunit, are activated at the synapse.