Abstract
Accumulating evidence indicate that GABA regulates activity-dependent development of inhibitory synapses in the vertebrate brain, but the underlying mechanisms remain unclear. Here we combined live imaging of cortical GABAergic axons with single cell genetic manipulation to dissect the role of presynaptic GABAB receptors (GABABRs) in inhibitory synapse formation in mouse. Developing GABAergic axons form a significant number of transient boutons but only a subset was stabilized. Synaptic vesicles in these nascent boutons are often highly mobile in the course of tens of minutes. Activation of presynaptic GABABRs stabilized mobile vesicles in nascent boutons through the local enhancement of actin polymerization. Inactivation of GABABRs in developing basket interneurons resulted in aberrant pattern of bouton size distribution, reduced bouton density and reduced axon branching, as well as reduced frequency of miniature inhibitory currents in postsynaptic pyramidal neurons. These results suggest that GABABRs along developing inhibitory axons act as a local sensor of GABA release and promote presynaptic maturation through increased recruitment of mobile vesicle pools. Such release-dependent validation and maturation of nascent terminals is well suited to sculpt the pattern of synapse formation and distribution along axon branches.
Highlights
Inhibitory synaptic innervation in the cerebral cortex is often characterized by specificity as well as robustness (Somogyi et al, 1998; Huang et al, 2007)
We found no significant difference in the proportion of functional syn-SEP puncta between WT and GABAB1−/− PV neurons in all size populations (Figure 1E), indicating that the lack of GABAB receptors (GABABRs), rather than impaired transmission, accounts for the decreased vesicle pool stability in GABAB1−/− neurons
Our study reveals that developing GABAergic axons form numerous transient boutons and a very small subset of these was stabilized
Summary
Inhibitory synaptic innervation in the cerebral cortex is often characterized by specificity as well as robustness (Somogyi et al, 1998; Huang et al, 2007). Fast-spiking basket interneurons selectively contact the soma and proximal dendrite of pyramidal neurons, and a single basket cell innervates hundreds of pyramidal neurons with tens of clustered perisomatic synapses on each target (Tamas et al, 1997; Chattopadhyaya et al, 2007). Inhibitory synapses often form in the absence of postsynaptic protrusions, GABAergic axons likely play a more active role in searching for and soliciting synaptic targets. Dendrite-targeting GABAergic synapses are formed exclusively at pre-existing axon-dendrite crossings without the involvement of dendritic protrusions (Wierenga et al, 2008)
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