What at AZD2281 mw first appeared to be almost unfathomable diversity and complexity is becoming more accessible as the ‘rules’ that apply to circuit

construction are elucidated. Dual intracellular recordings with dye-labelling have been very informative here. They have documented the vast range of properties displayed when different classes of synaptic connections are studied in detail and compared, each class displaying its own unique combination of properties (e.g. Thomson & Lamy, 2007 for review; see also Fig. 1). Synaptic connections are not made randomly with just any neuronal element that happens to be near to a particular axon. They involve only certain classes of target neurones and, moreover, specific subcellular compartments of those cells (Somogyi & Klausberger, 2005; Klausberger & Somogyi, 2008; for review of interneuronal axon targets; Thomson & Lamy, 2007, for review of pyramidal targets). These selective MK-1775 innervation patterns probably account for some of the GABAAR subtype segregation apparent in pharmacological and immunocytochemical studies, as each class of interneurone targets only certain subcompartments of its postsynaptic principal cell partners. In polarized epithelial cells, GABAARs containing the β1-subunit are sorted

to the apical membrane (Perez-Velazquez & Angelides, 1993) and β2/3-subunits to the basolateral membrane (Connolly et al., 1996a). Something similar appears to be happening in hippocampal pyramidal cells. Synapses supplied by basket cells (both PV- and CCK-containing) that innervate the soma and proximal dendrites of pyramidal cells were enhanced by low concentrations of Etomidate, an anaesthetic whose potency is greater at β2/3-subunit-containing GABAARs than at β1-subunit-containing GABAARs, but independent of the α-subunit included (Hill-Venning et al., 1997). When inputs to pyramidal cell dendrites acetylcholine supplied by bistratified cells were tested, however, they were very much less

sensitive to Etomidate (H. Pawelzik, unpublished data). It therefore appears that proximal GABAergic synapses on pyramidal cells are supplied with β2/3-subunit-containing GABAARs, while at least some dendritic synapses contain β1-subunit-containing GABAARs. Most synaptic GABAARs in cortical regions contain a γ2L-subunit; indeed, a γ2-subunit appears obligatory for synaptic receptors in cortical pyramidal cells (Essrich et al., 1998; Schweizer et al., 2003). The predominant class of extrasynaptic receptors contain a δ-subunit instead. In addition to the γ2-subunit most GABAARs are thought to contain two β-subunits and two α-subunits. Summarising simplistically, therefore, somatic synaptic GABAARs contain a γ2- and two β2/3-subunits, while at least some dendritic synaptic receptors contain a γ2- and two β1-subunits.