S Ko

(35-37)

Viable, fertile, slightly smaller litters, occasional seizures

Increased 72 Reduced a4

KO, knockout; 'these point mutations render the receptor insensitive to diazepam; DZ, diazepam.

KO, knockout; 'these point mutations render the receptor insensitive to diazepam; DZ, diazepam.

extrasynaptic, mediating tonic inhibition in response to GABA spill over from synaptic release sites. Thus 8 tends to specify extrasynaptic localization, and y 2 synaptic localization, but targeting is also influenced by the a subunit since a5 can direct y 2 to an extrasynaptic localization. Selective synaptic versus extrasynaptic distributions, for example of a1 and a2 versus a5, can occur in dissociated hippocampal cell culture and thus are not dependent on specific innervation patterns41. However, in vivo there is selective enrichment of different synaptic type subunits opposite different inputs. In pyramidal cell somata and proximal dendrites, whereas a1 subunits are enriched opposite parvalbumin-positive basket cells, a2 subunits are enriched opposite parvalbumin-negative cholecystokinin-positive basket cells42,43. These selective distributions may relate to the different physiological roles of a1 more in vigilance and memory and a2 more in anxiety related behavior as revealed by the H101R mutant mouse studies. Developmental and cell-type specific expression patterns may also be important. In adult hippocampus, a2 is high in pyramidal neurons and a1 highest in a subset of interneurons, whereas in neocortex a1 replaces a2,3 as the major a subunit during postnatal development44. The molecular basis for this richness in subcellular targeting patterns of GABAA receptor subunit combinations is not yet known. To generate selective targeting of a1 versus a2 opposite different types of basket cell terminals clearly requires input-specific signals, perhaps differential activity or perhaps axon-specific molecular cues.

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