Clustered Dynamics of Inhibitory Synapses and Dendritic Spines in the Adult Neocortex

Chen, Jerry L.; Villa, Katherine L.; Won, Jae Yon; So, Peter T. C.; Kubota, Yoshihiro; Nedivi, Elly

doi:10.1016/j.neuron.2012.02.030

Cited by 303 publications

(423 citation statements)

References 52 publications

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“…In vivo imaging of both dendritic spines and gephyrin clusters indicated that remodelling of spines and inhibitory shaft synapses is spatially clustered and monocular deprivation increased the frequency of clustering events 58 . These results indicate that the spatial relationship between synapses plays an important role in experiencedependent remodelling of cortical neuron connectivity.…”

Section: Discussionmentioning

confidence: 99%

Enhanced synapse remodelling as a common phenotype in mouse models of autism

et al. 2014

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Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.

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Section: Discussionmentioning

confidence: 99%

Enhanced synapse remodelling as a common phenotype in mouse models of autism

et al. 2014

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“…The notion that inhibitory synapses could also be structurally plastic and undergo continuous rearrangements is, however, much less understood. Recent in vivo studies have showed that sensory activity or ocular dominance plasticity are associated with important changes in the kinetics and clustering of dendritic inhibitory synapses (14,15,27). Here we focused on perisomatic inhibition, which is mainly mediated by parvalbumin interneurons and represents the main inhibitory input to hippocampal CA1 pyramidal neurons (28).…”

Section: Discussionmentioning

confidence: 99%

“…Gephyrin forms multimeric complexes that allow the anchoring of GABA A Rs (6) via molecular mechanisms that include phosphorylation and interactions with the guanine-nucleotide exchange factor collybistin (7)(8)(9)(10)(11)(12). In addition to changes in inhibitory strength, more recent in vivo experiments revealed that inhibitory synapses are also dynamic structures that can be formed and eliminated in response to sensory experience (13)(14)(15). The mechanisms implicated in the coordinated regulation of excitatory and inhibitory plasticity remain, however, poorly understood.…”

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confidence: 99%

Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation

Flores

Nikonenko

Méndez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

107

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Maintaining a proper balance between excitation and inhibition is essential for the functioning of neuronal networks. However, little is known about the mechanisms through which excitatory activity can affect inhibitory synapse plasticity. Here we used tagged gephyrin, one of the main scaffolding proteins of the postsynaptic density at GABAergic synapses, to monitor the activity-dependent adaptation of perisomatic inhibitory synapses over prolonged periods of time in hippocampal slice cultures. We find that learning-related activity patterns known to induce N-methyl-daspartate (NMDA) receptor-dependent long-term potentiation and transient optogenetic activation of single neurons induce within hours a robust increase in the formation and size of gephyrin-tagged clusters at inhibitory synapses identified by correlated confocal electron microscopy. This inhibitory morphological plasticity was associated with an increase in spontaneous inhibitory activity but did not require activation of GABA A receptors. Importantly, this activity-dependent inhibitory plasticity was prevented by pharmacological blockade of Ca 2+ /calmodulindependent protein kinase II (CaMKII), it was associated with an increased phosphorylation of gephyrin on a site targeted by CaMKII, and could be prevented or mimicked by gephyrin phosphomutants for this site. These results reveal a homeostatic mechanism through which activity regulates the dynamics and function of perisomatic inhibitory synapses, and they identify a CaMKIIdependent phosphorylation site on gephyrin as critically important for this process.inhibition | gabaergic synapse | plasticity | hippocampus | CaMKII S everal activity-dependent plasticity and homeostatic mechanisms (1, 2) contribute to regulate synaptic strength at excitatory synapses. Similar mechanisms are also expected to finely tune the level of inhibition in response to activity in individual neurons, but the mechanisms remain poorly understood. Different forms of plasticity at GABAergic synapses have been reported based on either presynaptic or postsynaptic mechanisms (3, 4). Similar to receptors at excitatory synapses, GABA A receptors (GABA A Rs), which mediate the fast component of inhibitory transmission, display complex trafficking mechanisms that affect the surface localization and diffusion of receptors (5). The distribution and clustering of GABA A Rs at synapses is tightly regulated through interactions with the scaffolding protein gephyrin, one of the main structural constituent of inhibitory postsynaptic densities. Gephyrin forms multimeric complexes that allow the anchoring of GABA A Rs (6) via molecular mechanisms that include phosphorylation and interactions with the guanine-nucleotide exchange factor collybistin (7-12). In addition to changes in inhibitory strength, more recent in vivo experiments revealed that inhibitory synapses are also dynamic structures that can be formed and eliminated in response to sensory experience (13-15). The mechanisms implicated in the coordinated regulation of excitatory an...

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“…However, the ability of synapses to undergo synaptic plasticity (48,49) and the local coordination of these rearrangements (50) indicate that α-Nrxn-mediated functions should be locally modulated. Here, we propose that the α-Nrxn-specific binding partner Nxph1 subserves such a modulatory role in subpopulations of synapses.…”

Section: Discussionmentioning

confidence: 99%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA B R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA B R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA B R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA A R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA B R and postsynaptic GABA A R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA A R and GABA B R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. synaptic transmission | thalamus | autism | neuroligin | ultrastructure

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Clustered Dynamics of Inhibitory Synapses and Dendritic Spines in the Adult Neocortex

Cited by 303 publications

References 52 publications

Enhanced synapse remodelling as a common phenotype in mouse models of autism

Enhanced synapse remodelling as a common phenotype in mouse models of autism

Activity-dependent inhibitory synapse remodeling through gephyrin phosphorylation

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

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