The smaller dendritic α5-GABAAR-mediated events are slowed in time course as they transfer to the soma and are difficult to identify from somatic Opaganib price recordings of spontaneous and miniature synaptic events. Their existence only becomes apparent in paired intracellular recordings. Other evidence for a largely extrasynaptic site for these GABAARs comes from recordings of ‘tonic’ inhibition, i.e. recordings of
a conductance that persists in the absence of action potential-elicited GABA release. However, many of these studies involve the use of GABA uptake inhibitors. The final piece of evidence is that α5-subunits are not typically colocalised with gephyrin, a postsynaptic scaffold protein originally thought to be present at, if not an essential component of, all GABAergic synapses. However, while gephyrin
is now considered important if not essential for clustering α2/3-GABAARs (Tretter selleck chemicals et al., 2008), it is not necessary for the clustering of α5-GABAARs in retina or spinal cord (Kneussel et al., 2001). The failure to find evidence for a synaptic location or role for a receptor subtype is not evidence for the absence of such a location or role. Some years ago, the weight of opinion was against a normal physiological synaptic role Amino acid for NMDA (N-methyl-d-aspartate) receptors, until, that is, the appropriate experiment was performed (Thomson et al., 1985). That specific GABAARs are located at specific synapses should, perhaps, not be surprising when it is remembered that glutamate receptors are largely found apposed to glutamatergic
boutons and GABA receptors apposed to GABAergic terminals. This is merely a finer level of detail. Moreover, presynaptic receptors can also be selectively inserted. Both the glutamatergic inputs from CA1 pyramidal cells (Shigemoto et al., 1996, 1997) and the GABAergic inputs from other interneurones (Somogyi et al., 2003) onto the OLM (oriens lacunosum moleculare) interneurones in CA1 stratum oriens are highly enriched in presynaptic mGluR7a receptors (metabotropic glutamate receptor type 7a), but these receptors are absent from the synaptic inputs onto other classes of interneurones or pyramidal cells in the same region. That is, the boutons supplied by a single axon will either express or not express a particular presynaptic receptor, depending on the type of neurone that is present postsynaptically. Specifically, how do postsynaptic neurones cluster just one type of GABAAR at each type of inhibitory synapse when, as is the case with CA1 pyramidal cells, they contain up to 10 different GABAAR subunits (α1, α2, α3, α4, α5, β1, β2, β3, γ2, δ).
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