Synaptic Competition Sculpts the Development of GABAergic Axo-Dendritic but Not Perisomatic Synapses

The neurotransmitter GABA regulates many aspects of inhibitory synapse development. We tested the hypothesis that GABA(A) receptors (GABA(A)Rs) work together with the synaptic adhesion molecule neuroligin 2 (NL2) to regulate synapse formation in different subcellular compartments. We investigated mice (gamma 2 knockdown mice'') with an engineered allele of the GABA(A)R gamma 2 subunit gene which produced a mosaic expression of synaptic GABAARs in neighboring neurons, causing a strong imbalance in synaptic inhibition. Deletion of the gamma 2 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 GABA(A)Rs. However, loss of the gamma 2 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, gamma 2-positive cells had increased axo-dendritic innervation compared with both gamma 2-negative and wild-type counterparts. Moreover heterologous synapses on spines, that are found after total deletion of GABA(A)Rs from all Purkinje cells, were rare in cerebella of gamma 2 knockdown mice. These findings reveal a selective role of gamma 2 subunit-containing GABA(A)Rs 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.