TY - JOUR
T1 - In the Telencephalon, GluN2C NMDA Receptor Subunit mRNA is Predominately Expressed in Glial Cells and GluN2D mRNA in Interneurons
AU - Alsaad, Hassan A.
AU - DeKorver, Nicholas W.
AU - Mao, Zhihao
AU - Dravid, Shashank M.
AU - Arikkath, Jyothi
AU - Monaghan, Daniel T.
N1 - Funding Information:
Fig. 10 Schematic diagram showing a potential role for GluN2C-containing NMDARs in the tripartite synapse. (1) l-Glutamate released from presynaptic nerve endings activates AMPA receptors and GluN2A-and/or GluN2B-containing NMDARs (NMDAR-2A/2B) on the postsynaptic dendrite. (2) With sufficient synaptic activation, glutamate spillover activates GluN2C-containing NMDARs (NMDAR-2C) and metabotropic glutamate receptors (mGluR) on the astrocyte, leading to increased cytoplasmic calcium levels from extracellular and intracellular sources, respectively. (3) In response to elevated intracellullar calcium from intracellular stores, and possibly from GluN2C currents, astrocytes release glutamate (and other gliotrans-mitters) which acts on extrasynaptic GluN2B-containing NMDARs (NMDAR-2B) on the postsynaptic structure on the same neuron, and potentially additional neurons, to modulate excitability and synaptic plasticity Acknowledgements This study was funded by the National Institutes of Health grants MH60252, NS104705, and GM110768 and the Edna Ittner Pediatric Research Foundation. The authors thank Dr. Andres Buonanno and colleagues for having provided the GluN2C-KO mouse line, Dr. Masahiko Watanabe for helpful discussions, Robin Taylor for expert graphical assistance, and Dr. Emily Harrison for technical advice.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - N-methyl-d-aspartate receptors (NMDARs) are widely distributed in the brain with high concentrations in the telencephalon where they modulate synaptic plasticity, working memory, and other functions. While the actions of the predominate GluN2 NMDAR subunits, GluN2A and GluN2B are relatively well understood, the function of GluN2C and GluN2D subunits in the telencephalon is largely unknown. To better understand the possible role of GluN2C subunits, we used fluorescence in situ hybridization (FISH) together with multiple cell markers to define the distribution and type of cells expressing GluN2C mRNA. Using a GluN2C-KO mouse as a negative control, GluN2C mRNA expression was only found in non-neuronal cells (NeuN-negative cells) in the hippocampus, striatum, amygdala, and cerebral cortex. For these regions, a significant fraction of GFAP-positive cells also expressed GluN2C mRNA. Overall, for the telencephalon, the globus pallidus and olfactory bulb were the only regions where GluN2C was expressed in neurons. In contrast to GluN2C, GluN2D subunit mRNA colocalized with neuronal and not astrocyte markers or GluN2C mRNA in the telencephalon (except for the globus pallidus). GluN2C mRNA did, however, colocalize with GluN2D in the thalamus where neuronal GluN2C expression is found. These findings strongly suggest that GluN2C has a very distinct function in the telencephalon compared to its role in other brain regions and compared to other GluN2-containing NMDARs. NMDARs containing GluN2C may have a specific role in regulating l-glutamate or d-serine release from astrocytes in response to l-glutamate spillover from synaptic activity.
AB - N-methyl-d-aspartate receptors (NMDARs) are widely distributed in the brain with high concentrations in the telencephalon where they modulate synaptic plasticity, working memory, and other functions. While the actions of the predominate GluN2 NMDAR subunits, GluN2A and GluN2B are relatively well understood, the function of GluN2C and GluN2D subunits in the telencephalon is largely unknown. To better understand the possible role of GluN2C subunits, we used fluorescence in situ hybridization (FISH) together with multiple cell markers to define the distribution and type of cells expressing GluN2C mRNA. Using a GluN2C-KO mouse as a negative control, GluN2C mRNA expression was only found in non-neuronal cells (NeuN-negative cells) in the hippocampus, striatum, amygdala, and cerebral cortex. For these regions, a significant fraction of GFAP-positive cells also expressed GluN2C mRNA. Overall, for the telencephalon, the globus pallidus and olfactory bulb were the only regions where GluN2C was expressed in neurons. In contrast to GluN2C, GluN2D subunit mRNA colocalized with neuronal and not astrocyte markers or GluN2C mRNA in the telencephalon (except for the globus pallidus). GluN2C mRNA did, however, colocalize with GluN2D in the thalamus where neuronal GluN2C expression is found. These findings strongly suggest that GluN2C has a very distinct function in the telencephalon compared to its role in other brain regions and compared to other GluN2-containing NMDARs. NMDARs containing GluN2C may have a specific role in regulating l-glutamate or d-serine release from astrocytes in response to l-glutamate spillover from synaptic activity.
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U2 - 10.1007/s11064-018-2526-7
DO - 10.1007/s11064-018-2526-7
M3 - Article
C2 - 29651654
AN - SCOPUS:85045240689
VL - 44
SP - 61
EP - 77
JO - Neurochemical Research
JF - Neurochemical Research
SN - 0364-3190
IS - 1
ER -