PUBLICATION
Developmental loss of NMDA receptors results in supernumerary forebrain neurons through delayed maturation of transit-amplifying neuroblasts
- Authors
- Napoli, A.J., Laderwager, S., Zoodsma, J.D., Biju, B., Mucollari, O., Schubel, S.K., Aprea, C., Sayed, A., Morgan, K., Napoli, A., Flanagan, S., Wollmuth, L.P., Sirotkin, H.I.
- ID
- ZDB-PUB-240211-5
- Date
- 2024
- Source
- Scientific Reports 14: 33953395 (Journal)
- Registered Authors
- Aprea, Christieann, Sirotkin, Howard
- Keywords
- KCC2, NMDA receptors, Neurodevelopmental disorders, Neurogenesis, Transit amplifying cells, Zebrafish
- MeSH Terms
-
- Animals
- Neural Stem Cells*/metabolism
- Neurogenesis/genetics
- Neurons/metabolism
- Receptors, N-Methyl-D-Aspartate*/genetics
- Receptors, N-Methyl-D-Aspartate*/metabolism
- Telencephalon/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 38336823 Full text @ Sci. Rep.
Citation
Napoli, A.J., Laderwager, S., Zoodsma, J.D., Biju, B., Mucollari, O., Schubel, S.K., Aprea, C., Sayed, A., Morgan, K., Napoli, A., Flanagan, S., Wollmuth, L.P., Sirotkin, H.I. (2024) Developmental loss of NMDA receptors results in supernumerary forebrain neurons through delayed maturation of transit-amplifying neuroblasts. Scientific Reports. 14:33953395.
Abstract
Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1-/-) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors. Focusing on the forebrain, we find that these fish have a progressive supernumerary neuron phenotype confined to the telencephalon at the end of embryonic neurogenesis, but which extends to all forebrain regions during postembryonic neurogenesis. This enhanced neuron population does not arise directly from increased numbers or mitotic activity of radial glia cells, the principal neural stem cells. Rather, it stems from a lack of timely maturation of transit-amplifying neuroblasts into post-mitotic neurons, as indicated by a decrease in expression of the ontogenetically-expressed chloride transporter, KCC2. Pharmacological blockade with MK-801 recapitulates the grin1-/- supernumerary neuron phenotype, indicating a requirement for ionotropic signaling. Thus, NMDA receptors are required for suppression of indirect, transit amplifying cell-driven neurogenesis by promoting maturational termination of mitosis. Loss of suppression results in neuronal overpopulation that can fundamentally change brain circuitry and may be a key factor in pathogenesis of neurodevelopmental disorders caused by NMDA receptor dysfunction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping