Synaptic competition sculpts the development of GABAergic axo-dendritic but not perisomatic synapses

• Published in: PloS one 2013-02, Vol.8 (2), p.e56311-e56311
• Main Authors: Frola, Elena, Patrizi, Annarita, Goetz, Thomas, Medrihan, Lucian, Petrini, Enrica Maria, Barberis, Andrea, Wulff, Peer, Wisden, William, Sassoè-Pognetto, Marco
• Format: Article
• Language: English
• Subjects: Animals; Artificial chromosomes; Axons - metabolism; Biology; Brain; Cell Adhesion Molecules, Neuronal - metabolism; Cerebellum; Clonal deletion; Compartments; Competition; Cortex; Dendrites - metabolism; Dendritic spines; GABA; gamma-Aminobutyric Acid - metabolism; Gene expression; Gene Knockdown Techniques; Genes; Genomes; Innervation; Localization; Medicine; Mice; Nerve Tissue Proteins - metabolism; Neurons; Neurosciences; Purkinje cells; Purkinje Cells - cytology; Purkinje Cells - metabolism; Pyramidal cells; Receptors; Receptors, GABA-A - deficiency; Receptors, GABA-A - genetics; Stem cells; Synapses; Synapses - metabolism; Synaptogenesis; Trends; γ-Aminobutyric acid A receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056311

The neurotransmitter GABA regulates many aspects of inhibitory synapse development. We tested the hypothesis that GABAA receptors (GABAARs) work together with the synaptic adhesion molecule neuroligin 2 (NL2) to regulate synapse formation in different subcellular compartments. We investigated mice ("γ2 knockdown mice") with an engineered allele of the GABAAR γ2 subunit gene which produced a mosaic expression of synaptic GABAARs in neighboring neurons, causing a strong imbalance in synaptic inhibition. Deletion of the γ2 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 GABAARs. However, loss of the γ2 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, γ2-positive cells had increased axo-dendritic innervation compared with both γ2-negative and wild-type counterparts. Moreover heterologous synapses on spines, that are found after total deletion of GABAARs from all Purkinje cells, were rare in cerebella of γ2 knockdown mice. These findings reveal a selective role of γ2 subunit-containing GABAARs 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.