Abstract
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 alpha(1) subunit during maturation of GABA-ergic transmission, using electrophysiology and immunohistochemistry in wild type (WT) and alpha(1)(0/0) mice and mice engineered to express diazepam-insensitive receptors (alpha(1H101R), alpha(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 alpha(4) and delta subunit occurred independently of the alpha(1) subunit. Subsequently (> or = P15), synaptic alpha(2) subunit/gephyrin clusters of WT VB neurones were replaced by those containing the alpha(1) subunit. Surprisingly, in alpha(1)(0/0) VB neurones the frequency of mIPSCs decreased between P12 and P27, because the alpha(2) 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 alpha(1) 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.