Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit
N-methyl-D-aspartate receptors (NMDARs) are ubiquitously expressed in the mammalian brain and are essential for neuronal development, survival and plasticity. GluN2 subunit composition has a profound effect on the properties of NMDARs. In substantia nigra dopaminergic (SNc-DA) neurons, pharmacologic...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-10-01
|
| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2018.00354/full |
| _version_ | 1819063390218223616 |
|---|---|
| author | Paul G. Morris Masayoshi Mishina Susan Jones |
| author_facet | Paul G. Morris Masayoshi Mishina Susan Jones |
| author_sort | Paul G. Morris |
| collection | DOAJ |
| description | N-methyl-D-aspartate receptors (NMDARs) are ubiquitously expressed in the mammalian brain and are essential for neuronal development, survival and plasticity. GluN2 subunit composition has a profound effect on the properties of NMDARs. In substantia nigra dopaminergic (SNc-DA) neurons, pharmacological experiments suggest that the relatively rare GluN2D subunits form functional synaptic and extrasynaptic NMDARs. Given the importance of establishing this point, mice lacking the GluN2D subunit (Grin2D-null) were used in this study to further explore the contribution of the GluN2D subunit to NMDAR responses. Significantly less DQP-1105-sensitive NMDAR-EPSC and significantly more ifenprodil-sensitive NMDAR-EPSC was observed in SNc-DA neurons from Grin2D-null mice, indicating that in these animals a small population of synaptic GluN2D subunits is replaced with GluN2B. Significantly larger currents were seen in response to higher concentrations (1–10 mM) of NMDA in SNc-DA neurons from Grin2D-null mice, as well as significantly more desensitization: these data are consistent with the presence of GluN2D-containing whole-cell NMDARs in SNc-DA neurons, with low conductance and little desensitization. Brief applications of NMDA evoked responses that were significantly less sensitive to DQP-1105 in slices from Grin2D-null mice. Tonic NMDAR activity in response to ambient extracellular glutamate, determined by the sensitivity of tonic current to D-AP5 (50 μM), was significantly less in SNc-DA neurons from Grin2D-null mice. In the presence of the glutamate transporter blocker TBOA (30 μM), the D-AP5-sensitive current was also significantly less in Grin2D-null mice. Taken together, these data support the evidence for GluN2D subunit expression in functional NMDARs at both synaptic and extrasynaptic locations in SNc-DA neurons. |
| first_indexed | 2024-12-21T15:13:55Z |
| format | Article |
| id | doaj.art-030261b3d647443aa021c32ed04086a9 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-21T15:13:55Z |
| publishDate | 2018-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-030261b3d647443aa021c32ed04086a92022-12-21T18:59:13ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-10-011210.3389/fncel.2018.00354396272Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D SubunitPaul G. Morris0Masayoshi Mishina1Susan Jones2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomBrain Science Laboratory, The Research Organization of Science and Technology, Ritsumeikan University, Shiga, JapanDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomN-methyl-D-aspartate receptors (NMDARs) are ubiquitously expressed in the mammalian brain and are essential for neuronal development, survival and plasticity. GluN2 subunit composition has a profound effect on the properties of NMDARs. In substantia nigra dopaminergic (SNc-DA) neurons, pharmacological experiments suggest that the relatively rare GluN2D subunits form functional synaptic and extrasynaptic NMDARs. Given the importance of establishing this point, mice lacking the GluN2D subunit (Grin2D-null) were used in this study to further explore the contribution of the GluN2D subunit to NMDAR responses. Significantly less DQP-1105-sensitive NMDAR-EPSC and significantly more ifenprodil-sensitive NMDAR-EPSC was observed in SNc-DA neurons from Grin2D-null mice, indicating that in these animals a small population of synaptic GluN2D subunits is replaced with GluN2B. Significantly larger currents were seen in response to higher concentrations (1–10 mM) of NMDA in SNc-DA neurons from Grin2D-null mice, as well as significantly more desensitization: these data are consistent with the presence of GluN2D-containing whole-cell NMDARs in SNc-DA neurons, with low conductance and little desensitization. Brief applications of NMDA evoked responses that were significantly less sensitive to DQP-1105 in slices from Grin2D-null mice. Tonic NMDAR activity in response to ambient extracellular glutamate, determined by the sensitivity of tonic current to D-AP5 (50 μM), was significantly less in SNc-DA neurons from Grin2D-null mice. In the presence of the glutamate transporter blocker TBOA (30 μM), the D-AP5-sensitive current was also significantly less in Grin2D-null mice. Taken together, these data support the evidence for GluN2D subunit expression in functional NMDARs at both synaptic and extrasynaptic locations in SNc-DA neurons.https://www.frontiersin.org/article/10.3389/fncel.2018.00354/fullNMDA receptorGluN2D subunitGluN2B subunitsubstantia nigradopamine neuronNMDAR-EPSC |
| spellingShingle | Paul G. Morris Masayoshi Mishina Susan Jones Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit Frontiers in Cellular Neuroscience NMDA receptor GluN2D subunit GluN2B subunit substantia nigra dopamine neuron NMDAR-EPSC |
| title | Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit |
| title_full | Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit |
| title_fullStr | Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit |
| title_full_unstemmed | Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit |
| title_short | Altered Synaptic and Extrasynaptic NMDA Receptor Properties in Substantia Nigra Dopaminergic Neurons From Mice Lacking the GluN2D Subunit |
| title_sort | altered synaptic and extrasynaptic nmda receptor properties in substantia nigra dopaminergic neurons from mice lacking the glun2d subunit |
| topic | NMDA receptor GluN2D subunit GluN2B subunit substantia nigra dopamine neuron NMDAR-EPSC |
| url | https://www.frontiersin.org/article/10.3389/fncel.2018.00354/full |
| work_keys_str_mv | AT paulgmorris alteredsynapticandextrasynapticnmdareceptorpropertiesinsubstantianigradopaminergicneuronsfrommicelackingtheglun2dsubunit AT masayoshimishina alteredsynapticandextrasynapticnmdareceptorpropertiesinsubstantianigradopaminergicneuronsfrommicelackingtheglun2dsubunit AT susanjones alteredsynapticandextrasynapticnmdareceptorpropertiesinsubstantianigradopaminergicneuronsfrommicelackingtheglun2dsubunit |