GRIN2C

This study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD.

We analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes. The MR analysis was performed by screening drug targets with MDD in the DrugBank database to explore the therapeutic targets for MDD. Inverse variance weighted (IVW), fixed-effect inverse variance weighted (FE-IVW), MR-Egger, weighted median, and weighted mode were used for complementary calculation.

The potential causal relationship between modifiable risk factors and depression contained 459 results for depression and 424 for MDD. Also, the associations between drug targets and MDD showed that SLC6A4, GRIN2A, GRIN2C, SCN10A, and IL1B expression are associated with an increased risk of depression. In contrast, ADRB1, CHRNA3, HTR3A, GSTP1, and GABRG2 genes are candidate protective factors against depression.

This study identified the risk factors causally associated with depression and MDD, and estimated 10 drug targets with significant impact on MDD, providing essential information for formulating strategies to prevent and treat depression.

NMDA receptors (NMDARs) modulate glutamatergic excitatory tone in the brain via two complementary modalities: a phasic excitatory postsynaptic current and a tonic extrasynaptic modality. Here, we demonstrated that the tonic extrasynaptic NMDAR- current (I_NMDA) mediated by NR2A-containing NMDARs is an efficient biosensor detecting the altered ambient glutamate level in the supraoptic nucleus (SON). I_NMDA of magnocellular neurosecretory cells (MNCs) measured by nonselective NMDARs antagonist, AP5, at holding potential (V_holding) -70 mV in low concentration of ECF Mg²⁺ ([Mg²⁺]_o) was transiently but significantly increased 1-week post induction of a DOCA (deoxycorticosterone) -salt hypertensive model rat. The I_NMDA uncovered by AP5 was compatible with that induced by a NR2A-selective antagonist, PEAQX (I_PEAQX) in both DOCA-H₂O (animals receive normal water after DOCA) and DOCA-salt (animals receive a mixture of 0.8% NaCl and 0.2% KCl in water after DOCA) groups. In agreement, NR2B antagonist, ifenprodil, or NR2C/D antagonist, PPDA, did not affect the holding current (I_holding) at V_holding -70 mV. Increased ambient glutamate by exogenous glutamate (10 μM) or glutamate transporter / excitatory amino acid transporters (EAATs) antagonist (TBOA, 50 μM) abolished the I_PEAQX difference between DOCA-H₂O and DOCA-salt group, suggesting that attenuated EAATs activity increased ambient glutamate concentration, leading to the larger I_PEAQX in DOCA-salt rats. In contrast, only ifenprodil but not PEAQX and PPDA uncovered I_NMDA at V_holding +40 mV under 1.2 mM [Mg²⁺]_o condition. I_ifenprodil was not different in DOCA-H₂O and DOCA-salt groups. Finally, NR2A, NR2B, and NR2D protein expression were not different in the SON of the two groups. Taken together, NR2A-containing NMDARs efficiently detected the increased ambient glutamate concentration in the SON of DOCA-salt hypertensive rats due to attenuated EAATs activity.Significance Statement The NMDAR-mediated excitatory tone between cells is transmitted via a phasic activation of synaptic NMDARs (EPSCs) and tonic activation of extrasynaptic NMDARs (I_NMDA) in the brain. The activation of NMDARs depends on the glutamate concentration, NMDAR subunit composition, and their subcellular localization, as well as the membrane potential. Therefore, the mechanism of NMDAR-mediated excitatory tone varies in different pathophysiological conditions. Our results show that the I_NMDA in non-depolarized and depolarized neurons is dominantly mediated by NR2A- and NR2B-containing NMDARs, respectively, and the former efficiently detects the ambient glutamate concentration in the supraoptic magnocellular neuroendocrine cells of normal and hypertensive rats. This study shows that NR2A-containing NMDARs could be a biosensor detecting ambient glutamate concentration in the brain.

Spinal cord injury (SCI) is one of the most devastating traumas, and the aberrant proliferation of astrocytes usually causes neurological deficits. However, the mechanism underlying astrocyte over-proliferation after SCI is unclear. Grin2c (glutamate ionotropic receptor type 2c) plays an essential role in cell proliferation. Our bioinformatic analysis indicated that Grin2c and Ca²⁺ transport functions were inhibited in astrocytes after SCI. Suppression of Grin2c stimulated astrocyte proliferation by inhibiting the Ca²⁺/calmodulin-dependent protein kinase 2b (CaMK2b) pathway in vitro. By screening different inflammatory factors, interleukin 1α (IL1α) was further found to inhibit Grin2c/Ca²⁺/CaMK2b and enhance astrocyte proliferation in an oxidative damage model. Blockade of IL1α using neutralizing antibody resulted in increased Grin2c expression and the inhibition of astrocyte proliferation post-SCI. Overall, this study suggests that IL1α promotes astrocyte proliferation by suppressing the Grin2c/Ca²⁺/CaMK2b pathway after SCI, revealing a novel pathological mechanism of astrocyte proliferation, and may provide potential targets for SCI repair.