NMDA Receptor Regulation Prevents Regression of Visual Cortical Function in the Absence of Mecp2
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SUMMARY Brain function is shaped by postnatal experience and vulnerable to disruption of Methyl-CpG-binding protein, Mecp2, in multiple neurodevelopmental disorders. How Mecp2 contributes to the experience-dependent refinement of specific cortical circuits and their impairment remains unknown. We analyzed vision in gene-targeted mice and observed an initial normal development in the absence of Mecp2. Visual acuity then rapidly regressed after postnatal day P35–40 and cortical circuits largely fell silent by P55-60. Enhanced inhibitory gating and an excess of parvalbumin-positive, perisomatic input preceded the loss of vision. Both cortical function and inhibitory hyperconnectivity were strikingly rescued independent of Mecp2 by early sensory deprivation or genetic deletion of the excitatory NMDA receptor subunit, NR2A. Thus, vision is a sensitive biomarker of progressive cortical dysfunction and may guide novel, circuit-based therapies for Mecp2 deficiency.
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Loss of vision is preceded by the accelerated development of Parvalbumin-expressing (PV+) fast-spiking basket cells that provide perisomatic inhibition to pyramidal cells.
“Loss of vision is preceded by the accelerated development of Parvalbuminexpressing (PV+) fast-spiking basket cells that provide perisomatic inhibition to pyramidal cells 125-127 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [125]
Vision acuity initially develops normally in Mecp2 mutants but regresses in young adult mice.
“In a pattern that resembles the relapse of RTT patients, vision acuity initially develops normally in Mecp2 mutants but regresses in young adult mice 125 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [125]
Inhibitory function seems to normalize in young adult mice, perhaps due to homeostatic compensations following long-term reduction of activity levels, but the early alterations in neural networks cause long-term functional deficits.
“Inhibitory function seems to normalize in young adult mice 129 , perhaps due to homeostatic compensations following long-term reduction of activity levels 126 , but the early alterations in neural networks cause long-term functional deficits 125 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [125]
The precocious window of critical period plasticity observed in Mecp2 mutant mice can be rescued by reducing sensory inputs (dark-rearing), decreasing the activation of PV+ interneurons by pyramidal cells (NMDA receptor disruption) or reducing GABAergic neurotransmission (Gad67 reduction).
“The precocious window of critical period plasticity observed in Mecp2 mutant mice (which reduces the influence of visual experience on the developing cortex) can be rescued by reducing sensory inputs (dark-rearing), decreasing the activation of PV+ interneurons by pyramidal cells (NMDA receptor disruption) or reducing GABAergic neurotransmission (Gad67 reduction) 125-127 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [125]
The abnormal activity of cortical circuits might be caused by the precocious development of GABAergic interneurons.
“Recent studies suggest that the abnormal activity of cortical circuits might be caused by the precocious development of GABAergic interneurons, a hypothesis that has been primarily tested in the visual cortex.”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [125]
Mecp2 mutants have a precocious onset and closure of critical period plasticity.
“Mecp2 mutants have a precocious onset and closure of critical period plasticity 125,126 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [125]
Visual acuity of MeCP2-null mice is comparable to WT at eye opening, as measured by optomotor task.
“Visual acuity of MeCP2 -/y mice is comparable to that of WT mice at the time of eye opening, as measured by an optomotor task (21).”
From MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex (2015) · cites this paper as [21]
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References 87 · Cited by 172
- Authors
- Durand, S., Patrizi, A., Quast, K. B., Hachigian, L., Pavlyuk, R., Saxena, A., Carninci, P., Hensch, T. K., & Fagiolini, M.
- Affiliations
- Boston Children's Hospital (US)
- RIKEN (JP)
- Corresponding author
- Fagiolini, Michela
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 76
- Issue
- 6
- Pages
- 1078-1090
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3733788
- OpenAlex
- W1999828796
- Cited by
- 172
- References
- 87
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 5 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 21 · 2019: 18 · 2018: 9 · 2017: 13 · 2016: 21 · 2015: 15 · 2014: 15 · 2013: 9
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP1OD003699)
- National Institute of Mental Health (T32MH020017)
- National Institute of Neurological Disorders and Stroke (R21NS062277, R01NS070300)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655, P30HD-18655)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- MeCP2, NMDA receptor, NR2A, visual cortex, parvalbumin interneurons, sensory deprivation, MeCP2 deficiency, neurodevelopmental disorders
- MeSH terms
- Animals, Disease Models, Animal, Female, Male, Nerve Degeneration, Neurons, Parvalbumins, Vision Tests, Visual Acuity, Visual Cortex, Visual Pathways, Rett Syndrome, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, Mice, Methyl-CpG-Binding Protein 2
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