PUBLICATION
A Model to Study NMDA Receptors in Early Nervous System Development
- Authors
- Zoodsma, J.D., Chan, K., Bhandiwad, A.A., Golann, D., Liu, G., Syed, S., Napoli, A., Burgess, H.A., Sirotkin, H.I., Wollmuth, L.P.
- ID
- ZDB-PUB-200422-22
- Date
- 2020
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 40(18): 3631-3645 (Journal)
- Registered Authors
- Burgess, Harold, Sirotkin, Howard
- Keywords
- none
- MeSH Terms
-
- Acoustic Stimulation/methods
- Animals
- Animals, Genetically Modified
- Excitatory Amino Acid Antagonists/pharmacology
- Female
- HEK293 Cells
- Humans
- Male
- Nervous System/drug effects
- Nervous System/embryology*
- Nervous System/metabolism*
- Photic Stimulation/methods
- Rats
- Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
- Receptors, N-Methyl-D-Aspartate/metabolism*
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/metabolism*
- PubMed
- 32245827 Full text @ J. Neurosci.
Citation
Zoodsma, J.D., Chan, K., Bhandiwad, A.A., Golann, D., Liu, G., Syed, S., Napoli, A., Burgess, H.A., Sirotkin, H.I., Wollmuth, L.P. (2020) A Model to Study NMDA Receptors in Early Nervous System Development. The Journal of neuroscience : the official journal of the Society for Neuroscience. 40(18):3631-3645.
Abstract
NMDARs are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca2+ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b Both grin1a-/- and grin1b-/- zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a-/-; grin1b-/-), which lack all NMDAR-mediated synaptic transmission, survive until ∼10 d after fertilization, providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system. SignificanceRapid communication between cells in the nervous system depends on ion channels that are directly activated by chemical neurotransmitters. One such ligand-gated ion channel, the NMDAR, impacts nearly all forms of nervous system function. It has been challenging, however, to study the prolonged absence of NMDARs in vertebrates, and hence their role in nervous system development, due to experimental limitations. Here, we demonstrate that zebrafish lacking all NMDAR transmission are viable through early development and are capable of a wide range of stereotypic behaviors. As such, this zebrafish model provides a unique opportunity to study the role of NMDAR in the development of the early vertebrate nervous system.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping