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Subunits of GABAA Receptor Regulates Inhibitory Synaptic Strength
Interdisciplinary Program in Neuroscience and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC 20007
Submitted 10 March 2004; accepted in final form 15 April 2004
Distinct 
subunit subtypes in the molecular assembly of GABAA receptors are a critical determinant of the functional properties of inhibitory synapses and their modulation by a range of pharmacological agents. We investigated the contribution of these subunits to the developmental changes of inhibitory synapses in cerebellar granule neurons in primary cultures from wild-type and 1 subunit –/– mice. The decay time of miniature inhibitory postsynaptic currents (mIPSCs) halved between 6 days in vitro (DIV6) and DIV12. This was paralleled by the decrease of 2 and 3 subunits, the increase of 1 and 6 subunits expression at synapses, and changes in the action of selective subunit modulators. A small but significant shortening of mIPSCs was observed with development in cells from –/– mice together with a decrease in the expression of 3 subunit. In contrast, the expression of 2 subunit at inhibitory synapses in –/– cells was significantly higher than in +/+ cells at DIV11-12. 5 subunit was not detected, and increased sensitivity to a selective 4/6 subunit agonist suggests increased expression of extrasynaptic receptors in –/– mice. 
2/3 subunit expression and loreclezole sensitivity increased with development in +/+ but not in –/– cells, supporting the preferential association of the 1 with the 2 subunit. Synaptic charge transfer strongly decreased with development but was not different between cells in the +/+ and –/– groups until DIV11-12. Our results uncover a pattern of sequential expression of subunits underlying the changes in functional efficacy of GABAergic networks with development.
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