Inhibitory Synapse Dynamics: Coordinated Presynaptic and Postsynaptic Mobility and the Major Contribution of Recycled Vesicles to New Synapse Formation

Overview

Journal J Neurosci

Specialty Neurology

Date 2011 Jul 22

PMID 21775594

Citations 53

Authors

Frederick A Dobie

Ann Marie Craig

Affiliations

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Abstract

Dynamics of GABAergic synaptic components have been studied previously over milliseconds to minutes, revealing mobility of postsynaptic scaffolds and receptors. Here we image inhibitory synapses containing fluorescently tagged postsynaptic scaffold Gephyrin, together with presynaptic vesicular GABA transporter (VGAT) or postsynaptic GABA(A) receptor γ2 subunit (GABA(A)Rγ2), over seconds to days in cultured rat hippocampal neurons, revealing modes of inhibitory synapse formation and remodeling. Entire synapses were mobile, translocating rapidly within a confined region and exhibiting greater nonstochastic motion over multihour periods. Presynaptic and postsynaptic components moved in unison, maintaining close apposition while translocating distances of several micrometers. An observed flux in the density of synaptic puncta partially resulted from the apparent merging and splitting of preexisting clusters. De novo formation of inhibitory synapses was observed, marked by the appearance of stably apposed Gephyrin and VGAT clusters at sites previously lacking either component. Coclustering of GABA(A)Rγ2 supports the identification of such new clusters as synapses. Nascent synapse formation occurred by gradual accumulation of components over several hours, with VGAT clustering preceding that of Gephyrin and GABA(A)Rγ2. Comparing VGAT labeling by active uptake of a luminal domain antibody with post hoc immunocytochemistry indicated that recycling vesicles from preexisting boutons significantly contribute to vesicle pools at the majority of new inhibitory synapses. Although new synapses formed primarily on dendrite shafts, some also formed on dendritic protrusions, without apparent interconversion. Altogether, the long-term imaging of GABAergic presynaptic and postsynaptic components reveals complex dynamics and perpetual remodeling with implications for mechanisms of assembly and synaptic integration.

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References

Liu G . Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites. Nat Neurosci. 2004; 7(4):373-9. DOI: 10.1038/nn1206. View

Studler B, Fritschy J, Brunig I . GABAergic and glutamatergic terminals differentially influence the organization of GABAergic synapses in rat cerebellar granule cells in vitro. Neuroscience. 2002; 114(1):123-33. DOI: 10.1016/s0306-4522(02)00206-3. View

Huang K, Sanders S, Singaraja R, Orban P, Cijsouw T, Arstikaitis P . Neuronal palmitoyl acyl transferases exhibit distinct substrate specificity. FASEB J. 2009; 23(8):2605-15. PMC: 2717768. DOI: 10.1096/fj.08-127399. View

Malinow R, Malenka R . AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002; 25:103-26. DOI: 10.1146/annurev.neuro.25.112701.142758. View

Kerschensteiner D, Morgan J, Parker E, Lewis R, Wong R . Neurotransmission selectively regulates synapse formation in parallel circuits in vivo. Nature. 2009; 460(7258):1016-20. PMC: 2746695. DOI: 10.1038/nature08236. View

Chen S, Karimi Tari P, She K, Haas K . Neurexin-neuroligin cell adhesion complexes contribute to synaptotropic dendritogenesis via growth stabilization mechanisms in vivo. Neuron. 2010; 67(6):967-83. DOI: 10.1016/j.neuron.2010.08.016. View

Sudhof T . Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008; 455(7215):903-11. PMC: 2673233. DOI: 10.1038/nature07456. View

Goda Y, Davis G . Mechanisms of synapse assembly and disassembly. Neuron. 2003; 40(2):243-64. DOI: 10.1016/s0896-6273(03)00608-1. View

Luscher B, Keller C . Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther. 2004; 102(3):195-221. DOI: 10.1016/j.pharmthera.2004.04.003. View

10.

Bresler T, Shapira M, Boeckers T, Dresbach T, Futter M, Garner C . Postsynaptic density assembly is fundamentally different from presynaptic active zone assembly. J Neurosci. 2004; 24(6):1507-20. PMC: 6730341. DOI: 10.1523/JNEUROSCI.3819-03.2004. View

11.

Darcy K, Staras K, Collinson L, Goda Y . Constitutive sharing of recycling synaptic vesicles between presynaptic boutons. Nat Neurosci. 2006; 9(3):315-21. DOI: 10.1038/nn1640. View

12.

Siddiqui T, Craig A . Synaptic organizing complexes. Curr Opin Neurobiol. 2010; 21(1):132-43. PMC: 3016466. DOI: 10.1016/j.conb.2010.08.016. View

13.

Hartman K, Pal S, Burrone J, Murthy V . Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons. Nat Neurosci. 2006; 9(5):642-9. DOI: 10.1038/nn1677. View

14.

Tretter V, Jacob T, Mukherjee J, Fritschy J, Pangalos M, Moss S . The clustering of GABA(A) receptor subtypes at inhibitory synapses is facilitated via the direct binding of receptor alpha 2 subunits to gephyrin. J Neurosci. 2008; 28(6):1356-65. PMC: 6671568. DOI: 10.1523/JNEUROSCI.5050-07.2008. View

15.

Rao A, Cha E, Craig A . Mismatched appositions of presynaptic and postsynaptic components in isolated hippocampal neurons. J Neurosci. 2000; 20(22):8344-53. PMC: 6773189. View

16.

Ruthazer E, Li J, Cline H . Stabilization of axon branch dynamics by synaptic maturation. J Neurosci. 2006; 26(13):3594-603. PMC: 6673865. DOI: 10.1523/JNEUROSCI.0069-06.2006. View

17.

Kimberley McAllister A . Dynamic aspects of CNS synapse formation. Annu Rev Neurosci. 2007; 30:425-50. PMC: 3251656. DOI: 10.1146/annurev.neuro.29.051605.112830. View

18.

Fritschy J, Harvey R, Schwarz G . Gephyrin: where do we stand, where do we go?. Trends Neurosci. 2008; 31(5):257-64. DOI: 10.1016/j.tins.2008.02.006. View

19.

Telgkamp P, Padgett D, Ledoux V, Woolley C, Raman I . Maintenance of high-frequency transmission at purkinje to cerebellar nuclear synapses by spillover from boutons with multiple release sites. Neuron. 2004; 41(1):113-26. DOI: 10.1016/s0896-6273(03)00802-x. View

20.

Triller A, Choquet D . Surface trafficking of receptors between synaptic and extrasynaptic membranes: and yet they do move!. Trends Neurosci. 2005; 28(3):133-9. DOI: 10.1016/j.tins.2005.01.001. View