MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex

May combine two claims.

At P15, MeCP2-null V1 has more PNNs around PV cells, especially in infragranular layers, than WT; WT 13.0 ± 3.2 vs MeCP2-null 31.1 ± 4.1 PNN/0.6 mm2, P=0.0009.

“In P15 MeCP2 -/y V1, however, WFA signals were already distinct, and PV cells were surrounded by PNNs especially in infragranular layers (Fig. 3 C and D) (numbers of PNN/0.6 mm 2 in WT were 13.0 ± 3.2 and in MeCP2 -/y : 31.1 ± 4.1, P value = 0.0009).”

May combine two claims.

In ~P30 MeCP2-null mice, evoked and spontaneous firing rates in vivo are not significantly different from WT.

“Furthermore, in ∼P30 MeCP2 -/y mice, the evoked (Fig. S8A) and spontaneous (Fig. S8B) firing rates in vivo were not significantly different from WT controls,”

May combine two claims.

GAD65 puncta and VGAT are increased in MeCP2-null V1.

“In addition, immunofluorescence puncta for GAD65 (Fig. 1 G-I), the other GABA synthetic enzyme, specifically localized to presynaptic terminals, and vesicular GABA transporter (VGAT) were also increased (Fig. 1 J-L).”

May combine two claims.

In MeCP2-null mice, monocular deprivation from P15 to P20 induces a significant ocular dominance shift, while MD from P26 has no effect.

“However, in MeCP2 -/y mice, MD from P15 to P20 induced a significant OD shift (Fig. 6 A and D, Right) but had no effect at the normal peak of the critical period (i.e., from P26; Fig. 6 C and E, Right).”

May combine two claims.

Reduction of GAD67 expression using Gad1 heterozygote is sufficient to rescue the expression pattern of multiple GABAergic markers and the early onset of the critical period.

“Importantly, we demonstrate that a reduction of GAD67 expression using Gad1 heterozygote is sufficient to rescue the expression pattern of multiple GABAergic markers and the early onset of the critical period.”

May combine two claims.

At P15, mIPSC amplitude is significantly increased in PV cells but not in pyramidal neurons in MeCP2-null V1.

“we found a significant increase in mIPSC amplitude in PV cells (Fig. S4 A and B), consistent with in- creased GAD67 and GAD65 expression in MeCP2 -/y V1 intern- eurons. Interestingly, there was no increase in mIPSC amplitude in PyNs (Fig. S4 D and E).”

May combine two claims.

In MeCP2-null; Gad1+/- V1, monocular deprivation from P15 to P19 induces no ocular dominance plasticity, unlike MeCP2-null V1.

“Furthermore, MD from P15 to P19 induced no OD plasticity in MeCP2 -/y ; Gad +/-V1, similar to WT mice and in sharp contrast to MeCP2 -/y (Fig. 8H).”

May combine two claims.

In WT mice, monocular deprivation from P26 induces a significant ocular dominance shift, while MD from P15 to P20 has no effect.

“As expected, MD in WT mice from P26 induced a significant OD shift (Fig. 6 A, B, and E, Left), whereas MD from P15 to P20 had no effect (Fig. 6 A and D, Left).”

May combine two claims.

The degree of binocular orientation matching in ~P30 MeCP2-null mice is significantly worse than age-matched WT and remains at a pre-critical-period level.

“The degree of matching in ∼P30 MeCP2 -/y mice was significantly worse than agematched WTs (which had reached the adult level by P30, Fig. 7L) and in fact remained at a level preceding the critical period (∼P20 WT mice) and similar to that observed after long-term visual deprivation from birth (42).”

• cites [42] sourceNot checked yet

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May combine two claims.

By postnatal day 15, WFA labeling is weak and diffuse in wild-type primary visual cortex, whereas well-formed perineuronal nets, especially around parvalbumin-positive neurons in infragranular layers, are present in MeCP2-deficient primary visual cortex.

“By P15, weak and diffuse labeling of WFA (green) in WT (A and B) compared with wellformed PNNs, especially around PV + neurons (red) in infragranular layers [layers 5 (L5) and 6 (L6) marked at Top] of MeCP2 -/y V1 (C and D).”

May combine two claims.

By postnatal day 30, WFA staining begins to delineate more well-formed structures in wild-type primary visual cortex, while perineuronal nets in MeCP2-deficient primary visual cortex are already well-formed and numerous.

“By P30, WFA staining begins to delineate more well-formed structures in WT V1 (E and F), whereas PNNs in MeCP2 -/y V1 are already well-formed and numerous (G and H).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

An example wild-type neuron showed orientation-selective responses through the contralateral and ipsilateral eye and matched orientation tuning between the two eyes.

“An example WT neuron showing orientation selective responses through the contralateral (Contra, A) and ipsilateral (Ipsi, B) eye, and matched orientation tuning between the two eyes.”

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

At postnatal day 30, in the primary visual cortex of MeCP2-deficient mice, GAD67 and parvalbumin expression in the somata of GABAergic neurons in infragranular layers is higher than in wild-type mice.

“GAD67 (green) and PV (red) expression in the soma of GABAergic neurons in infragranular layers was higher in MeCP2 -/y compared with WT.”

May combine two claims.

An example MeCP2-deficient neuron showed sharp orientation tuning monocularly but a mismatch between the two eyes.

“An example MeCP2 -/y neuron showing sharp orientation tuning monocularly, but mismatch between the two eyes.”

May combine two claims.

In MeCP2-deficient primary visual cortex at postnatal day 15, the time course of activation across all layers is similar to that of wild-type at postnatal day 30 and is significantly reduced compared with wild-type at postnatal day 15.

“The time course of activation in MeCP2 -/y at P15 (green) across all layers is similar to WT-P30 and significantly reduced compared with WT-P15.”

Classified as probably not a substantial claim. May combine two claims.

MeCP2 is a methyl-CpG binding protein involved in regulating neuronal chromatin architecture and gene transcription, especially in response to neural activity and experience after birth.

“M ECP2 is a methyl-CpG binding protein implicated in the regulation of neuronal chromatin architecture and gene transcription (1)(2)(3)(4), especially in response to neural activity and experience during postnatal life (5,6).”

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Mutations in MeCP2 cause Rett syndrome, an autism spectrum-associated disorder.

“Mutations in the MeCP2 gene cause Rett syndrome (RTT) (7), an autism spectrum disorder.”

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May combine two claims.

The precocious critical period in MeCP2-null mice reduces the influence of visual experience on developing V1 and compromises experience-dependent circuit wiring and visual function.

“In our study, we further demonstrate that the precocious critical period in MeCP2 -/y mice, which reduces the influence of visual experience on the developing V1, compromises experience-dependent circuit wiring and visual function: orientation tuning of individual binocular neurons in mature MeCP2 -/y V1 remain unmatched between the two eyes.”

May combine two claims.

Shortly after eye opening, V1 neurons exhibit orientation tuning and respond to both eyes, but orientation preference is binocularly mismatched; this mismatch is progressively corrected through visual experience during the critical period.

“Shortly after eye opening, V1 neurons exhibit orientation tuning and respond to stimulus to both eyes, but the orientation preference is binocularly mismatched.This initial mismatch is then progressively corrected through visual experience during the critical period, such that individual binocular neurons become tuned to similar orientations through the two eyes (42),”

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May combine two claims.

The reduction in synaptic depression between PV cells in MeCP2-null V1 likely reflects enhanced GABA transmission between PV-PV cells or altered release probability.

“This reduction likely results from an enhancement of GABA transmission between PV-PV cells or a change in release probability.”

May combine two claims.

The enhancement of GABA transmission among PV cells at P15 suggests earlier physiological maturation of these cells and may provide more robust inhibitory control over V1 activity.

“An enhancement of GABA transmission among PV cells at P15 would suggest an earlier physiological maturation of these cells which, as a more coherent network, would likely provide more robust inhibitory control over the spatiotemporal flow and processing of neural activity in V1.”

May combine two claims.

The precocious critical period in MeCP2-null mice is correlated with and possibly contributes to aberrant V1 wiring and deficient visual perception.

“Therefore, the precocious critical period in MeCP2 -/y mice, which reduces the influence of visual experience on the developing V1, is correlated with and possibly contributes to aberrant wiring of V1 circuits and deficient visual perception.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

Similar mechanisms may operate in other cortical areas to achieve proper integration of behaviorally relevant sensory-motor inputs or social-emotional information during corresponding critical periods.

“similar mechanisms may operate in other cortical areas to achieve proper integration of behaviorally relevant sensory-motor inputs or of neuronal pathways that carry appropriate social-emotional information during their corresponding critical periods.”

Classified as probably not a substantial claim. May combine two claims.

Maturation of GABAergic inhibition during the precritical period in the third postnatal week is necessary to initiate the critical period, which peaks in the fourth week and closes shortly after.

“Maturation of GABAergic inhibition during this “precritical period” in the third postnatal week is necessary to initiate the critical period, which peaks in the fourth week and closes shortly after (16).”

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Classified as probably not a substantial claim. May combine two claims.

Visual cortices from at least three animals were used for each developmental stage and genotype, and at least four sagittal sections containing visual cortex from each animal were analyzed.

“Visual cortices from at least three animals were used for each developmental stage and genotype.At least four sagittal sections containing the visual cortex from each animal were analyzed.”

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

Brains were processed blind to genotype and together at all steps to minimize variability.

“Brains were processed blind to the genotype and together at all steps in the process (perfusions, sectioning, immunostaining, and imaging) to minimize variability.”

May combine two claims.

MeCP2 mutations affect basic aspects of visual function, which might impact acquisition of proper social-behavioral abilities.

“Our results suggest that MeCP2 mutations affect basic aspects of visual function, which might impact acquisition of proper socialbehavioral abilities.”

May combine two claims.

Gad1 is among the earliest genes misregulated in V1 of germ-line MeCP2-null mice and likely sets in motion a cascade of cellular and circuitry alterations.

“Our results suggest that Gad1 is among the earliest genes misregulated in V1 of germ-line MeCP2 -/y mice, which likely sets in motion a cascade of cellular and circuitry alterations.”

May combine two claims.

A precocious increase of GABA transmission in V1 and precocious maturation of PV cells trigger an earlier onset of the critical period, whereas an accelerated rise of PNNs results in earlier closure.

“A precocious increase of GABA transmission in V1 and precocious maturation of PV cells trigger an earlier onset (18,41), whereas an accelerated rise of PNNs results in an earlier closure of the critical period (27).”

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Classified as probably not a substantial claim. May combine two claims.

GAD67 expression is highly sensitive to input and network activity and directly impacts magnitude of GABAergic transmission.

“As a rate-limiting GABA synthetic enzyme, GAD67 expression is highly sensitive to input and network activity and directly impacts the magnitude GABAergic transmission (43,48).”

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Classified as probably not a substantial claim.

Maturation of GABAergic inhibition mediated by fast-spiking PV interneuron network is crucial for triggering onset and regulating progression of critical period for functional wiring in V1.

“It is now well established, largely from studies in rodent primary visual cortex, that the maturation of GABAergic inhibition mediated by a fast-spiking PV interneuron network is a crucial mechanism for triggering the onset and regulating the progression of the critical period for functional wiring in V1 (16,46).”

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

GAD67 and GAD65 form complexes with vGAT on synaptic vesicles, facilitating coupling from GABA synthesis to vesicular packaging.

“It should be noted that, in addition to mediating cytosolic GABA synthesis, which influences cellular GABA levels, GAD67 and GAD65 form complexes that directly interact with vGAT on synaptic vesicles, thereby facilitating the coupling from GABA synthesis to vesicular packaging (51,52).”

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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The mechanisms underlying experience-triggered and MECP2-regulated PV interneuron maturation and critical period timing may also apply to other cortical areas and functional modalities.

“The mechanisms that underlie experience-triggered and MECP2-regulated PV interneuron maturation and critical period timing may also apply to other cortical areas and functional modalities.”

May combine two claims.

The spatiotemporal profile of signal propagation in P15 MeCP2-null V1 resembles that of WT V1 at P30, suggesting accelerated maturation of cortical circuit operation.

“The spatiotemporal profile of signal propagation in P15 MeCP2 -/y mice appeared more similar to that of WT V1 at P30, suggesting an accelerated maturation of the cortical circuit operation.”

May combine two claims.

Mature PNNs are inhibitory for experience-dependent plasticity; their increase correlates with critical period termination and removal in adult V1 restores plasticity.

“Mature PNN is inhibitory for experience-dependent plasticity: its increase in developing V1 correlates with the termination of the critical period and its removal in adult V1 restores plasticity (27,31,32).”

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May combine two claims.

Both the onset and closure of the critical period for ocular dominance plasticity are accelerated in MeCP2-null mice.

“Taken together, both the onset and closure of the critical period for OD plasticity were accelerated in MeCP2 -/y mice.”

Classified as probably not a substantial claim. May combine two claims.

Mice with incompletely sealed eyelids or with indications of corneal damage or cataracts were excluded before imaging.

“Mice whose eyelids were not completely sealed close or those with any indication of corneal damage or cataracts were excluded from the study before imaging.”

Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

Voltage-sensitive dye recordings were performed and analyzed with blinding to genotype.

“Recordings were performed and analyzed blind to the genotype.”

May combine two claims.

At the retinogeniculate synapse of MeCP2-null mice, initial synapse formation proceeds normally between P9 and P21, but subsequent experience-dependent synapse remodeling goes awry.

“It is of interest to note that at the retinogeniculate synapse of MeCP2 -/y mice, the initial phase of synapse formation proceeds normally (between P9 and P21) but the subsequent experiencedependent phase of synapse remodeling goes awry (58).”

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May combine two claims.

Once initiated, critical period plasticity rises, peaks, and terminates with a relatively fixed schedule, in part defined by molecular markers including PNNs.

“On the other hand, once initiated, critical period plasticity rises, peaks, and terminates with a rather fixed schedule (16), in part defined by several molecular markers including those that mark PNNs (29).”

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

A recent study using conditional deletion of MeCP2 in PV cells during the third to fourth postnatal week reported an absence of critical period plasticity.

“A recent study using conditional deletion of MeCP2 in PV cells during the third to fourth postnatal week reported an absence of critical period plasticity (60).”

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

Quantifications of marker expression are not comparable across ages because settings appropriate for each age were selected.

“As the expression levels of these markers increase during development, settings appropriate for each ages were selected for quantification; thus quantifications are not comparable across ages.”

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

Data were grouped and compared statistically only after the animal's genotype was revealed.

“Data were grouped and compared statistically after the genotype of the animal was revealed.”

Classified as probably not a substantial claim.

All control animals used for comparison with mutant mice were wild-type littermates.

“All control animals were WT littermates for the mutant mice.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Rett patients have more difficulty reading emotional expressions than counterparts, linked to atypical eye scanning.

“In fact, Djukic et al. (63) reported recently that Rett patients have more difficulty reading emotional expressions than their counterparts and these problems are linked to atypical eye scanning.”

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

An accelerated maturation of the PV network has been shown to trigger an early onset of the critical period.

“An accelerated maturation of the PV network has been shown to trigger an early onset of the critical period (18,59).”

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Classified as probably not a substantial claim.

A previous study reported a deficit in glutamatergic synapse maturation and more protracted OD plasticity in V1 in adult MeCP2 heterozygous females.

“A previous study reported a deficit in glutamatergic synapse maturation and more protracted OD plasticity in V1 in adult MeCP2 heterozygous females (62).”

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