Frola_2013_PLoS.One_8_e56311

The neurotransmitter GABA regulates many aspects of inhibitory synapse development. We tested the hypothesis that GABA receptors (GABARs) work together with the synaptic adhesion molecule neuroligin 2 (NL2) to regulate synapse formation in different subcellular compartments. We investigated mice ("gamma2 knockdown mice") with an engineered allele of the GABAR gamma2 subunit gene which produced a mosaic expression of synaptic GABARs in neighboring neurons, causing a strong imbalance in synaptic inhibition. Deletion of the gamma2 subunit did not abolish synapse formation or the targeting of NL2 to distinct types of perisomatic and axo-dendritic contacts. Thus synaptic localization of NL2 does not require synaptic GABARs. However, loss of the gamma2 subunit caused a selective decrease in the number of axo-dendritic synapses on cerebellar Purkinje cells and cortical pyramidal neurons, whereas perisomatic synapses were not significantly affected. Notably, gamma2-positive cells had increased axo-dendritic innervation compared with both gamma2-negative and wild-type counterparts. Moreover heterologous synapses on spines, that are found after total deletion of GABARs from all Purkinje cells, were rare in cerebella of gamma2 knockdown mice. These findings reveal a selective role of gamma2 subunit-containing GABARs in regulating synapse development in distinct subcellular compartments, and support the hypothesis that the refinement of axo-dendritic synapses is regulated by activity-dependent competition between neighboring neurons.