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Cited by 176Neurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology ResearchVisual perception and processing mechanisms

Choroid-Plexus-Derived Otx2 Homeoprotein Constrains Adult Cortical Plasticity

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Spatazza, Julien, Lee, Henry H.C., Di Nardo, Ariel A., Tibaldi, Lorenzo, Joliot, Alain, Hensch, Takao K., Prochiantz, Alain·2013·Cell Reports
DOI 10.1016/j.celrep.2013.05.014PMC PMC4119931
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Abstract

Brain plasticity is often restricted to critical periods in early life. Here, we show that a key regulator of this process in the visual cortex, Otx2 homeoprotein, is synthesized and secreted globally from the choroid plexus. Consequently, Otx2 is maintained in selected GABA cells unexpectedly throughout the mature forebrain. Genetic disruption of choroid-expressed Otx2 impacts these distant circuits and in the primary visual cortex reopens binocular plasticity to restore vision in amblyopic mice. The potential to regulate adult cortical plasticity through the choroid plexus underscores the importance of this structure in brain physiology and offers therapeutic approaches to recovery from a broad range of neurodevelopmental disorders.

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Crossref · 10.1016/j.celrep.2013.05.014

Cites

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Claims the paper makes

0 of 28 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Otx2 is expressed in the choroid plexus of adult mice, including the lateral, fourth, and third ventricles.

    “In situ hybridization on adult brain sections confirmed the expression of Otx2 in the choroid plexus of the lateral and fourth ventricles (Fig. 2A and insets A1-2), as well as third ventricle (not shown).”
    Quote in the paperSubstantial claim
  • Findingown data

    TrkB, a transmembrane protein expressed in choroid plexus, is not detected in adult mouse cerebrospinal fluid.

    “In contrast TrkB, also expressed in the choroid plexus (Timmusk et al., 1995), is not detected in the CSF sample (Fig. 2C).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Timmusk et al., 1995 source

      Not checked in the free run.

  • Findingown data

    After choroid plexus recombination in adult mice later than P90, Otx2 level in visual cortex layers III/IV decreases to a level similar to that at critical period opening at P21.

    “The decrease of Otx2 in layers III/IV of the visual cortex after recombination in the adult choroid plexus later than P90 is illustrated (Western blot) and quantified in Figure 3M. Comparison with the time course of Otx2 accumulation in layer III/IV containing PV-cells (Fig. 3N) demonstrates that following recombination the level of Otx2 is similar to that observed at CP opening (P21).”
    Quote in the paperSubstantial claim
  • Findingown data

    Otx2 protein is present in cerebrospinal fluid collected from adult mice.

    “Fig. 2C reveals the presence of both Otx2 and TTR in the CSF.”
    Quote in the paperSubstantial claim
  • Findingown data

    In adult cortical regions where Otx2 protein is present but the Otx2 locus is inactive, most Otx2-stained cells also express parvalbumin.

    “In all cortical regions where the protein was present but the locus inactive, the vast majority of Otx2-stained cells also expressed PV (Fig. 1M).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.
  • Classified as probably not a substantial claim. 7
  • May combine two claims. 23

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Mean Otx2 staining intensity per cell is similar across brain regions regardless of whether Otx2 expression is cell autonomous.

    “The mean intensity of Otx2 staining per cell was similar in all regions independent of whether Otx2 activity was cell autonomous or not, even though a slightly higher expression may be seen in the cell autonomous regions (Fig.1N).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.

  • May combine two claims.

    Findingown data

    Otx2 mRNA expression by choroid plexus increases only slightly between P7 and P90, and total Otx2 protein shows a similar pattern.

    “Interestingly, Otx2 mRNA expression (RT-PCR) by the choroid plexus increased only slightly between P7 and P90 (Fig. 3O); a similar pattern was seen for total Otx2 protein (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Choroid plexus Otx2 knockdown does not alter calretinin-positive cell number or mean intensity in binocular visual cortex.

    “Neither the number of calretinin-positive cells (Fig. 3D, I, K; 93.9 ± 2.3 %, p > 0.05) nor their mean intensity (Fig. 3L; Vehicle, 100 ± 1.5 vs CRE-Tat, 101.7 ± 1.5, p > 0.4) was altered, indicating a PV-cell specific effect.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.

  • May combine two claims.

    Findingown data

    Surface-associated Otx2 protein and Otx2 in cerebrospinal fluid remain roughly constant before and after the visual critical period.

    “This constant expression before and after the visual CP was also seen at the level of surface associated Otx2 protein (4.6 % pre-CP and 5.4 % post-CP), as well as for Otx2 in the CSF (Fig. 3P), even though the low amounts of protein in the CSF (see above) make quantification difficult.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Otx2 protein is present across prefrontal, auditory, somatosensory, and visual cortices and in limbic structures including basolateral amygdala and hippocampal CA1 of adult brain.

    “immunohistochemistry (Fig. 1E-L) revealed Otx2 protein across prefrontal, auditory, somatosensory and visual cortices as well as limbic structures (basolateral amygdala BLA, hippocampal CA1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.

  • May combine two claims.

    Findingown data

    Otx2 transcripts are absent throughout the adult cortex but are present in dorsal thalamus and superior colliculus.

    “We now confirmed by in situ hybridization that Otx2 transcripts are not found anywhere throughout the adult cortex (Fig. 1A-D), while evident in dorsal thalamus (dLGN) and superior colliculus as expected (Fig. 1B2, C2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CRE-Tat does not modify total neuron number in basolateral amygdala or GABA-stained cell number and intensity in visual cortex, discounting cell death.

    “Importantly, the total number of neurons identified by NeuN-staining was not modified in BLA (100.5 ± 9.1%, p > 0.4; n=6 for each group) nor that of GABA-stained cells in V1 or the intensity of GABA staining (Fig. 3E, J, K, L; Cell number: 100.3 ± 1.3%, p > 0.4; Intensity: Vehicle, 100 ± 2.1 vs CRE-Tat, 100.7 ± 2.1, p > 0.4; n=8 for each group), thus discounting the possibility of cell death in”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.

  • May combine two claims.

    Findingown data

    CRE-Tat treatment decreases Otx2 mRNA and protein content in choroid plexus compared with vehicle, while not significantly changing these parameters in retina, dLGN, or superior colliculus.

    “Accordingly, a strong and specific decrease in both Otx2 mRNA and protein content (Fig. 2I) was observed in the choroid plexus of CRE-Tat treated animals when compared to vehicle-treated animals (mRNA: Vehicle, 1.00 ± 0.056 VS CRE-Tat, 0.36 ± 0.056, p=0.022 / Protein: Vehicle, 1.00 ± 0.065 VS CRE-Tat, 0.24 ± 0.049, p=0.028), while these parameters were not significantly different from control in”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Choroid plexus Otx2 knockdown reduces the number of Otx2-positive cells and their mean fluorescence intensity in binocular visual cortex.

    “Indeed, a significant reduction in the number of Otx2-positive cells and their mean fluorescence intensity was observed in the binocular visual cortex (V1b) of CRE-Tat treated animals compared to vehicle (Fig. 3A, F, K, L; cell number: 68.1 ± 3.7%, p = 0.002; mean intensity per cell: Vehicle, 100 ± 1.2 vs CRE-Tat, 82.9 ± 1.2, p = 0.0008).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.

  • May combine two claims.

    Study design and conductown data

    Injection of cell-permeable CRE-Tat into lateral ventricles of adult ROSA26R reporter mice produces high recombination in choroid plexus and no recombination in dLGN or superior colliculus.

    “The efficiency of recombination tested five days after a single injection was very high, as demonstrated by the substantial LacZ expression in the choroid plexus (Fig. 2D-F). This access to the choroid plexus was extremely specific as illustrated by the absence of recombination in the dLGN and Superior Colliculus (Fig. 2F-G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Otx2 in cerebrospinal fluid is unlikely to come from cellular contamination and instead reflects secretion from the choroid plexus.

    “The absence of membrane-bound protein, TrkB, in these conditions makes it unlikely that Otx2 in the CSF reflects cellular contamination, but rather secretion from the choroid plexus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    In Otx2flox/flox mice, CRE-Tat injection causes specific genomic rearrangement in choroid plexus but not in retina, dLGN, or superior colliculus.

    “Even though the genomic rearrangement in the choroid plexus was not complete, it was specific and did not affect the retina, dLGN or Superior Colliculus (Fig. 2H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Early sensory experience initiates expression of Otx2 binding sites on nascent perineuronal nets, facilitating Otx2 import and opening a period of plasticity.

    “The model also stipulates that early sensory experience (sensory input) initiates expression of Otx2 binding sites on nascent PNNs (Beurdeley et al., 2012; Miyata et al., 2012), facilitating Otx2 import and opening a period of plasticity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Beurdeley et al., 2012 source

      Not checked in the free run.

    • cites Miyata et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In dopaminergic neurons and retinal ganglion cell growth cones, translation of nuclear-encoded mitochondrial mRNAs commonly occurs after homeoprotein capture.

    “Indeed, translation of nuclear-encoded mitochondrial mRNAs commonly follows homeoprotein capture by dopaminergic neurons or retinal ganglion cell growth cones (Alvarez-Fischer et al., 2011; Stettler et al., 2012; Yoon et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Alvarez-Fischer et al., 2011 source

      Not checked in the free run.

    • cites Stettler et al., 2012 source

      Not checked in the free run.

    • cites Yoon et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The choroid plexus, acting through cerebrospinal fluid, may regulate critical-period plasticity generally, including in the amygdala, auditory cortex, and prefrontal cortex, which have critical periods that are shifted or shorter than that of primary visual cortex.

    “Thus, one striking implication is that the choroid plexus, via the CSF, may be a general regulator of CP plasticity, including the amygdala (Gogolla et al., 2009), auditory (Barkat et al., 2011) or prefrontal cortex (Belforte et al., 2010; Yang et al., 2012) – structures with shifted or shorter critical periods than V1.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gogolla et al., 2009 source

      Not checked in the free run.

    • cites Barkat et al., 2011 source

      Not checked in the free run.

    • cites Belforte et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    PCR was used to verify that CRE-induced recombination occurred efficiently at the genomic DNA level.

    “PCR was used to confirm the efficiency of CRE-induced recombination at the level of genomic DNA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Activity-dependent critical period opening may require transport of Otx2 along the visual pathway and ensuing initial maturation of parvalbumin cells marked by perineuronal net assembly.

    “The activity-dependent CP opening may thus require the transport of Otx2 along the visual pathway and ensuing initial maturation of PV-cells marked by PNN assembly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Plasticity during development and in adulthood is regulated by Otx2 import, and perineuronal nets are the gatekeepers of Otx2.

    “Overall, one can propose that plasticity during development and in the adult is regulated by Otx2 import and that PNNs are the gatekeepers of Otx2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Hydrolysis of chondroitin sulfates reopens plasticity in adult rat visual cortex, which may be explained in part by the persistent role of perineuronal nets in Otx2 transport into parvalbumin cells.

    “The finding that hydrolysis of chondroitin sulfates reopens plasticity in the adult rat visual cortex may thus be explained, in part, by the persistent role of PNNs in Otx2 transport into PV-cells (Pizzorusso et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pizzorusso et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Subsequent Otx2 internalization increases intracellular Otx2 and parvalbumin-cell maturation, reflected by further parvalbumin expression and perineuronal net assembly, until a second threshold closes plasticity.

    “Subsequent Otx2 internalization increases intracellular Otx2 and PV-cell maturation reflected by further PV expression and PNN assembly (Sugiyama et al., 2008) until a second threshold is reached that closes plasticity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sugiyama et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A general source, through mature fully assembled perineuronal nets, participates in maintaining a non-plastic state, allowing the possibility to reopen plasticity in adulthood.

    “The same scheme also explain show a general source, thanks to mature, fully assembled PNNs, participates in maintaining a non-plastic state, allowing for the possibility to reopen plasticity in adulthood (Beurdeley et al., 2012; Pizzorusso et al., 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Beurdeley et al., 2012 source

      Not checked in the free run.

    • cites Pizzorusso et al., 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    CSF samples with any detectable blood contamination were discarded.

    “Any samples contaminated with the slightest traces of blood were discarded.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Otx2 present in parvalbumin cells outside visual cortex favors a more general source, supported by the choroid plexus.

    “The observation that Otx2 is present in PV-cells outside the visual cortex (Fig. 1) favors amore general source, supported here by the choroid plexus.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Perineuronal nets may protect parvalbumin cells from oxidative stress.

    “which may be protected by PNNs (Cabungcal et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cabungcal et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parvalbumin-cell maturation in dark-reared animals is rescued by direct Otx2 infusion, leading to specific accumulation in parvalbumin cells and critical period opening.

    “Instead, PV-cell maturation in dark-reared animals is rescued by direct Otx2 infusion leading to its specific accumulation in PV-cells and CP opening (Sugiyama et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sugiyama et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Parvalbumin cells are highly susceptible to oxidative stress in several cognitive disorders.

    “Correspondingly, PV-cells are highly vulnerable to oxidative stress across a number of cognitive disorders (Do et al., 2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Do et al., 2009

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    A key target of Otx2 may be the increased ATP metabolism found in fast-spiking cells.

    “An important Otx2 target may be the enriched ATP metabolism in these fast-spiking cells (Plessy et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Plessy et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Plasticity may be activated at a low Otx2 threshold and then actively repressed in adulthood by continuous transfer of choroid-derived Otx2 into mature parvalbumin cells after a second threshold is passed.

    “Taken together, plasticity may be activated at a low Otx2 threshold and then actively repressed in adulthood by the continuous transfer of choroid-derived Otx2 into mature PV-cells after a second threshold has been passed.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Visually evoked potential recordings validly measure visual acuity and visual cortical function.
    • Rests on an assumption: Long-term monocular deprivation in mice produces an amblyopia-like condition relevant to human amblyopia.

  • May combine two claims.

    Premisecitation

    In dark-reared animals, the opening of plasticity does not take place, and Otx2 and parvalbumin levels remain low in parvalbumin cells.

    “Moreover, the opening of plasticity (first threshold) does not take place in dark-reared animals, where the Otx2 and PV levels remain low in PV-cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sugiyama et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Direct infusion of Otx2 before critical period opening opens the critical period ahead of time and also closes it ahead of time.

    “In support of the hypothesis is that direct infusion of Otx2 before CP opening opens CP ahead of time and also closes it ahead of time (Sugiyama et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sugiyama et al., 2008 source

      Not checked in the free run.

30 of 30

  • The paper relies on this without support.

    The Otx2 antibody used for immunohistochemistry specifically detects Otx2 protein.

    “immunohistochemistry (Fig. 1E-L) revealed Otx2 protein across prefrontal, auditory, somatosensory and visual cortices as well as limbic structures (basolateral amygdala BLA, hippocampal CA1).”

  • The paper relies on this without support.

    Visually evoked potential recordings validly measure visual acuity and visual cortical function.

    “we used visually-evoked potential (VEP) recordings to measure visual acuity.”

  • The paper relies on this without support.

    Long-term monocular deprivation in mice produces an amblyopia-like condition relevant to human amblyopia.

    “The therapeutic value of reducing choroid-derived Otx2 was further confirmed by monitoring recovery from amblyopia induced earlier in life.”
3 of 3

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Authors
Spatazza, J., Lee, H. H. C., Di Nardo, A. A., Tibaldi, L., Joliot, A., Hensch, T. K., & Prochiantz, A.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Boston Children's Hospital (US)
Corresponding author
  • Hensch, Takao K.
  • Prochiantz, Alain
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2013-06
Volume
3
Issue
6
Pages
1815-1823
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2013.05.014
PMC
PMC4119931
OpenAlex
W2097469682
Cited by
176
References
48
Citations by year
2026: 4 · 2025: 12 · 2024: 9 · 2023: 12 · 2022: 12 · 2021: 17 · 2020: 20 · 2019: 17 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 21 · 2014: 12 · 2013: 7
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Collège de France
  • National Institutes of Health (1 DP1 OD 003699)
  • National Institute of Mental Health (5P50MH094271)
  • Agence Nationale de la Recherche (2009-00424, ANR-10-BLAN-141-01, ANR-11-BLAN-069467)
  • Croucher Foundation
  • Ministry of Education, Science and Technology
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Visual perception and processing mechanisms
Keywords
Otx2, choroid plexus, critical period, amblyopia, primary visual cortex, GABAergic interneurons, neurodevelopmental disorders, visual recovery
MeSH terms
Animals, Choroid Plexus, Humans, Mice, Inbred C57BL, Neuronal Plasticity, Mice, Otx Transcription Factors

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