Abstract
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.
Highlights
During development neurotransmission regulates synapse formation and guides the selective assembly of circuitry
We found no significant differences in the density of neuroligin 2 (NL2) clusters outlining the profile of c2-positive, c2-negative and WT pyramidal cells, suggesting that perisomatic innervation of cortical neurons is not regulated by synaptic GABAA receptors (GABAARs) (Fig. 8B)
To investigate the importance of GABAergic signaling in synapse development, we have taken advantage of an engineered gabrg2 mouse allele that strongly reduced the expression of synaptic GABAARs
Summary
During development neurotransmission regulates synapse formation and guides the selective assembly of circuitry. Synapse heterogeneity is exemplified by the numerous types of GABAergic synapses that target distinct subcellular domains (somatic, dendritic or axonal) of principal neurons [9,10,11] How these selective connections are generated during brain development and how their number is controlled is only partially understood [12,13]. The interpretation of this result was complicated, because PCs express transiently a3-GABAARs at a time when perisomatic synapses form [18] These findings imply that GABAergic activity has a selective effect on inhibitory synapse formation in separate types of neuron and/or different neuronal compartments
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