Progressive maturation of silent synapses governs the duration of a critical period

Huang, Xiaojie; Stodieck, Sophia Katharina; Goetze, Bianka; Cui, Lei; Wong, Man Ho; Wenzel, Colin; Hosang, Leon; Dong, Yan; Löwel, Siegrid; Schlüter, Oliver M.

doi:10.1073/pnas.1506488112

Cited by 96 publications

(193 citation statements)

References 74 publications

(120 reference statements)

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“…Notably, no changes in GABAergic or NMDA receptor currents are observed, suggesting that the reactivation of plasticity by PSD-95 deletion lies downstream of the regulation of inhibitory circuitry. A conversion of ‘silent’ to functional synapses has been proposed as a general mechanism to constrain plasticity across brain regions (Greifzu et al, 2014; Huang et al, 2015). …”

Section: Molecular Reactivation Of Critical Period In Adulthoodmentioning

confidence: 99%

Critical periods in amblyopia

2018

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The shift in ocular dominance (OD) of binocular neurons induced by monocular deprivation is the canonical model of synaptic plasticity confined to a postnatal critical period. Developmental constraints on this plasticity not only lend stability to the mature visual cortical circuitry but also impede the ability to recover from amblyopia beyond an early window. Advances with mouse models utilizing the power of molecular, genetic, and imaging tools are beginning to unravel the circuit, cellular, and molecular mechanisms controlling the onset and closure of the critical periods of plasticity in the primary visual cortex (V1). Emerging evidence suggests that mechanisms enabling plasticity in juveniles are not simply lost with age but rather that plasticity is actively constrained by the developmental up-regulation of molecular ‘brakes’. Lifting these brakes enhances plasticity in the adult visual cortex, and can be harnessed to promote recovery from amblyopia. The reactivation of plasticity by experimental manipulations has revised the idea that robust OD plasticity is limited to early postnatal development. Here, we discuss recent insights into the neurobiology of the initiation and termination of critical periods and how our increasingly mechanistic understanding of these processes can be leveraged toward improved clinical treatment of adult amblyopia.

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Section: Molecular Reactivation Of Critical Period In Adulthoodmentioning

confidence: 99%

Critical periods in amblyopia

2018

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“…Accordingly, PSD-95 KO mice exhibit lifelong ODP (Huang et al, 2015). Interestingly, defects of PV + INs disrupting CP mechanisms were found in V1 of MeCP2 null mice (Krishnan et al, 2015), and conditional deletion of MeCP2 in PV + cells completely abolished CP plasticity (He et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex

Pizzo

Gurgone

Castroflorio

et al. 2016

Front. Cell. Neurosci.

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Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5−/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5−/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5−/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development.

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“…Because these modifications are assumed to underlie the development of amblyopia, excitatory synapses represent strong candidate targets for its treatment. Indeed, recent reports have revealed that changes in the levels of the excitatory postsynaptic density protein PSD-95 govern the duration of the critical period for ocular dominance (OD) plasticity in the visual cortex, independent of changes in inhibitory circuits (Huang et al, 2015). PSD-95 expression increases in the visual cortex during the critical period for OD plasticity and promotes the progressive maturation of the so-called “silent” synapses that contain only NMDA-type glutamate receptors and that lack AMPA receptors.…”

Section: New Molecular/pharmacological and Genetic Approachesmentioning

confidence: 99%

“…Genetic loss of PSD-95 function leads to the persistence of silent synapses, allowing the juvenile form of OD plasticity to be maintained lifelong. Strikingly, using a viral gene silencing approach to reduce PSD-95 in the visual cortex of adult mice rejuvenates excitatory synapses by reinstating silent synapses like those in the immature cortex and reopens a critical period for visual cortical plasticity (Huang et al, 2015). …”

Section: New Molecular/pharmacological and Genetic Approachesmentioning

confidence: 99%

“…Inhibition of HDACs can also reinstate plasticity in the adult visual cortex to allow recovery from amblyopia (Putignano et al, 2007; Silingardi et al, 2010). Finally, an increase in AMPA-silent synapses (white synaptic boutons) underlies the heightened plasticity following knock-out or virus-mediated gene silencing of PSD-95 (Huang et al, 2015). Silent synapses also persist in the adult visual cortex in dark-reared mice (Funahashi et al, 2013).…”

Section: Figmentioning

confidence: 99%

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Amblyopia: New molecular/pharmacological and environmental approaches

Stryker

Löwel

2018

Vis Neurosci

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Emerging technologies are now giving us unprecedented access to manipulate brain circuits, shedding new light on treatments for amblyopia. This research is identifying key circuit elements that control brain plasticity and highlight potential therapeutic targets to promote rewiring in the visual system during and beyond early life. Here, we explore how such recent advancements may guide future pharmacological, genetic, and behavioral approaches to treat amblyopia. We will discuss how animal research, which allows us to probe and tap into the underlying circuit and synaptic mechanisms, should best be used to guide therapeutic strategies. Uncovering cellular and molecular pathways that can be safely targeted to promote recovery may pave the way for effective new amblyopia treatments across the lifespan.

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Progressive maturation of silent synapses governs the duration of a critical period

Cited by 96 publications

References 74 publications

Critical periods in amblyopia

Critical periods in amblyopia

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex

Amblyopia: New molecular/pharmacological and environmental approaches

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