Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits
Open accessAbstract
Background Early postnatal experience shapes NMDA receptor (NMDAR) subunit composition and kinetics at excitatory synapses onto pyramidal cells; however, little is known about NMDAR maturation onto inhibitory interneurons. Methods We combined whole-cell patch clamp recordings (n=440) of NMDAR-mediated currents from layer 4-to-2/3 synapses onto pyramidal and GFP-labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30 & 45 postnatal days) with array tomography 3-D reconstructions of NMDAR subunits GluN2A- and GluN2B-positive synapses onto PV cells. Results We show that the trajectory of the NMDAR subunit switch is slower in parvalbumin-positive (PV) interneurons than in excitatory pyramidal cells in visual cortex. Notably, this differential time course is reversed in the absence of methyl-CpG-binding protein, MeCP2, the molecular basis for cognitive decline in Rett syndrome and some cases of autism. Additional genetic reduction of GluN2A subunits, which prevents regression of vision in Mecp2-knockout mice, specifically rescues the accelerated NMDAR maturation in PV cells. Conclusion We demonstrate: (1) the time course of NMDAR maturation is cell-type specific and (2) a new cell-type specific role for Mecp2 in the development of NMDAR subunit composition. Reducing GluN2A expression in Mecp2-deficient mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus, circuit-bas…
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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 [127]
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 [127]
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 [127]
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Self-citation
- Authors
- Mierau, S. B., Patrizi, A., Hensch, T. K., & Fagiolini, M.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Fagiolini, Michela
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 79
- Issue
- 9
- Pages
- 746-754
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4670611
- OpenAlex
- W942876669
- Cited by
- 50
- References
- 5
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 12 · 2018: 7 · 2017: 2 · 2016: 4 · 2015: 1
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NRSA (T32)
- Nancy Lurie Marks Foundation
- International Rett Syndrome Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- MeCP2, GluN2A, GluN2B, parvalbumin interneurons, pyramidal neurons, visual cortex, Rett syndrome, postnatal development, Mecp2 knockout mice, autism spectrum disorder, cortical circuits
- MeSH terms
- Animals, Female, Interneurons, Male, Membrane Potentials, Mice, Inbred C57BL, Parvalbumins, Synapses, Visual Cortex, Receptors, N-Methyl-D-Aspartate, Pyramidal Cells, Mice, Knockout, Protein Subunits, Mice, Methyl-CpG-Binding Protein 2
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