Dataset Information

Presynaptic GABA(B) Receptor Regulates Activity-Dependent Maturation and Patterning of Inhibitory Synapses through Dynamic Allocation of Synaptic Vesicles.

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 GABA(B) receptors (GABA(B)Rs) 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 GABA(B)Rs stabilized mobile vesicles in nascent boutons through the local enhancement of actin polymerization. Inactivation of GABA(B)Rs 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 GABA(B)Rs 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.

SUBMITTER: Fu Y

PROVIDER: S-EPMC3512030 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Presynaptic GABA(B) Receptor Regulates Activity-Dependent Maturation and Patterning of Inhibitory Synapses through Dynamic Allocation of Synaptic Vesicles.

Fu Yu Y Wu Xiaoyun X Lu Jiangteng J Huang Z Josh ZJ

Frontiers in cellular neuroscience 20121203

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 GABA(B) receptors (GABA(B)Rs) in inhibitory synapse formation in mouse. Developing GABAergic axons form a significant number of transient boutons but only a subset was stabilized. Synaptic vesi ...[more]

PMID: 23227002

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Project description:The descending auditory system modulates the ascending system at every level. The final descending, or efferent, stage comprises lateral olivocochlear and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC-mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB-MOC synapses exhibit short-term depression, suggesting reduced MNTB-MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound-evoked activity in MNTB neurons in vivo, MNTB-MOC synapses may be tonically depressed. To probe this, we characterized short-term plasticity of MNTB-MOC synapses in mouse brain slices. We mimicked in vivo-like temperature and extracellular calcium conditions, and in vivo-like activity patterns of fast synaptic activation rates, sustained activation and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, postsynaptic currents in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression. KEY POINTS: Inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) onto medial olivocochlear (MOC) neurons exhibit short-term plasticity that is sensitive to calcium and temperature, with enhanced synaptic depression occurring at higher calcium concentrations and at room temperature. High rates of background synaptic activity that mimic the upper limits of spontaneous MNTB activity cause tonic synaptic depression of MNTB-MOC synapses that limits further synaptic inhibition. High rates of activity at MNTB-MOC synapses cause synaptic summation with concurrent depression to yield a response with an initial large amplitude that decays to a tonic inhibition.

Project description:Adaptive forms of synaptic plasticity that reduce excitatory synaptic transmission in response to prolonged increases in neuronal activity may prevent runaway positive feedback in neuronal circuits. In hippocampal neurons, for example, glutamatergic presynaptic terminals are selectively silenced, creating "mute" synapses, after periods of increased neuronal activity or sustained depolarization. Previous work suggests that cAMP-dependent and proteasome-dependent mechanisms participate in silencing induction by depolarization, but upstream activators are unknown. We, therefore, tested the role of calcium and G-protein signaling in silencing induction in cultured hippocampal neurons. We found that silencing induction by depolarization was not dependent on rises in intracellular calcium, from either extracellular or intracellular sources. Silencing was, however, pertussis toxin sensitive, which suggests that inhibitory G-proteins are recruited. Surprisingly, blocking four common inhibitory G-protein-coupled receptors (GPCRs) (adenosine A(1) receptors, GABA(B) receptors, metabotropic glutamate receptors, and CB(1) cannabinoid receptors) and one ionotropic receptor with metabotropic properties (kainate receptors) failed to prevent depolarization-induced silencing. Activating a subset of these GPCRs (A(1) and GABA(B)) with agonist application induced silencing, however, which supports the hypothesis that G-protein activation is a critical step in silencing. Overall, our results suggest that depolarization activates silencing through an atypical GPCR or through receptor-independent G-protein activation. GPCR agonist-induced silencing exhibited dependence on the ubiquitin-proteasome system, as was shown previously for depolarization-induced silencing, implicating the degradation of vital synaptic proteins in silencing by GPCR activation. These data suggest that presynaptic muting in hippocampal neurons uses a G-protein-dependent but calcium-independent mechanism to depress presynaptic vesicle release.

Dataset Information

Presynaptic GABA(B) Receptor Regulates Activity-Dependent Maturation and Patterning of Inhibitory Synapses through Dynamic Allocation of Synaptic Vesicles.

Publications

Presynaptic GABA(B) Receptor Regulates Activity-Dependent Maturation and Patterning of Inhibitory Synapses through Dynamic Allocation of Synaptic Vesicles.

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