Developmental maturation of synaptic and extrasynaptic GABA_A receptors in mouse thalamic ventrobasal neurones

Thalamic ventrobasal (VB) relay neurones express multiple GABA_A receptor subtypes mediating phasic and tonic inhibition. During postnatal development, marked changes in subunit expression occur, presumably reflecting changes in functional properties of neuronal networks. The aims of this study were to characterize the properties of synaptic and extrasynaptic GABA_A receptors of developing VB neurones and investigate the role of the α 1 subunit during maturation of GABA-ergic transmission, using electrophysiology and immunohistochemistry in wild type (WT) and α₁ ^0/0 mice and mice engineered to express diazepam-insensitive receptors (α_1H101R, α_2H101R). In immature brain, rapid (P8/9-P10/11) developmental change to mIPSC kinetics and increased expression of extrasynaptic receptors (P8-27) formed by the α₄ and δ subunit occurred independently of the α₁ subunit. Subsequently (≥ P15), synaptic α₂ subunit/gephyrin clusters of WT VB neurones were replaced by those containing the α₁ subunit. Surprisingly, in α₁^0/0 VB neurones the frequency of mIPSCs decreased between P12 and P27, because the α₂ subunit also disappeared from these cells. The loss of synaptic GABA_A receptors led to a delayed disruption of gephyrin clusters. Despite these alterations, GABA-ergic terminals were preserved, perhaps maintaining tonic inhibition. These results demonstrate that maturation of synaptic and extrasynaptic GABA_A receptors in VB follows a developmental programme independent of the α₁ subunit. Changes to synaptic GABA_A receptor function and the increased expression of extrasynaptic GABA_A receptors represent two distinct mechanisms for fine-tuning GABA-ergic control of thalamic relay neurone activity during development.