Abstract
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.
Highlights
N-methyl-D-aspartate receptors (NMDARs) are ubiquitous at mammalian brain excitatory synapses, where they are opened by co-incident detection of glutamate, glycine/D-serine and depolarization to relieve their Mg2+ ion block (Traynelis et al, 2010)
GluN2D subunit expression is prominent in the brainstem and diencephalon in neonates but decreases throughout development; in mature neurons, it is reported in some cerebellar nuclei, the striatum, the olfactory bulb, substantia nigra dopaminergic (SNc-DA) neurons, subthalamic nucleus (STN) neurons, and hippocampal interneurons (Watanabe et al, 1993, 1994; Monyer et al, 1994; Standaert et al, 1994; Wenzel et al, 1995, 1997; Misra et al, 2000; Brickley et al, 2003; Lozovaya et al, 2004; Jones and Gibb, 2005; Brothwell et al, 2008; Harney et al, 2008; Suárez et al, 2010; Mullasseril et al, 2010; Swanger et al, 2015; von Engelhardt et al, 2015; Perszyk et al, 2016)
At least 10 EPSCs immediately before, and 10 EPSCs in the presence of D-AP5 (AMPAR-EPSC) were averaged and the AMPAR-EPSC was subtracted from the total-EPSC to give the NMDAR-EPSC (Figure 2A)
Summary
N-methyl-D-aspartate receptors (NMDARs) are ubiquitous at mammalian brain excitatory synapses, where they are opened by co-incident detection of glutamate, glycine/D-serine and depolarization to relieve their Mg2+ ion block (Traynelis et al, 2010). GluN2D subunit expression is prominent in the brainstem and diencephalon in neonates but decreases throughout development; in mature neurons, it is reported in some cerebellar nuclei, the striatum, the olfactory bulb, substantia nigra dopaminergic (SNc-DA) neurons, subthalamic nucleus (STN) neurons, and hippocampal interneurons (Watanabe et al, 1993, 1994; Monyer et al, 1994; Standaert et al, 1994; Wenzel et al, 1995, 1997; Misra et al, 2000; Brickley et al, 2003; Lozovaya et al, 2004; Jones and Gibb, 2005; Brothwell et al, 2008; Harney et al, 2008; Suárez et al, 2010; Mullasseril et al, 2010; Swanger et al, 2015; von Engelhardt et al, 2015; Perszyk et al, 2016)
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