AMPA receptor x GRIK

Nerve agents are lethal chemical weapons and highly potent chemoconvulsants. For the treatment of nerve agent-induced status epilepticus (SE), the FDA has approved the use of benzodiazepines-initially diazepam and recently midazolam (MDZ); however, benzodiazepines are not neuroprotective, particularly if not administered promptly. Here, we compared the antiseizure and neuroprotective efficacy of MDZ with that of tezampanel (LY293558; an AMPA/GluK1 receptor antagonist) administered with caramiphen (CRM; an antagonist of muscarinic and NMDA receptors), 30 min after the onset of SE induced by exposure of young-adult male and female rats to the nerve agent soman; neuropathology assessments were conducted from 7 days to 6 months post-exposure. Latency to suppression of the initial SE was comparable after MDZ or LY293558 + CRM treatment. However, seizures reoccurred, and MDZ-treated rats had longer SE, followed by significant neurodegeneration, neuronal and interneuronal loss in the CA1 hippocampal area and the basolateral amygdala, hippocampal and amygdalar atrophy, reduced spontaneous IPSCs in the basolateral amygdala, increased anxiety, and spontaneous recurrent seizures (SRS). MDZ-treated males had longer SE than MDZ-treated females and lower 24-h and long-term survival. MDZ-treated females displayed delayed hippocampal neurodegeneration and atrophy, as well as delayed SRS. Males and females treated with LY293558 + CRM presented minimal neurodegeneration and only delayed appearance of brain damage, without significant sex differences. The results suggest that MDZ treatment may carry higher risks for males. Replacing benzodiazepines with antiglutamatergic first-line treatments to prevent long-term brain damage and associated morbidities is overdue; LY293558 + CRM has produced remarkably promising results.

Oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes throughout life. Many cues modulate OPC proliferation and differentiation, including neuronal activity, which OPCs sense through voltage-gated ion channels and glutamate receptors. However, OPCs display regional and temporal diversity in the membrane surface expression of these channels and receptors, altering their capacity to sense and respond to neuronal activity. Here, we use whole-cell patch-clamp in acute brain slices and bath-apply 3 μM kainate or 10 μM AMPA to investigate the heterogeneity in kainate and AMPA receptor membrane surface expression. We find that, while kainate receptor current density remains stable with age, OPCs do not respond to neuronal kainate receptor-specific drugs. In contrast, AMPA receptor current density differs with age and between regions, likely due to altered Ca²⁺ permeability and receptor desensitization. The temporal changes in AMPA-evoked currents in OPCs correlate with reported age-related changes in proliferation and differentiation potential.

Proper testicular development is essential for spermatogenesis, a complex biological process that depends on the continuous proliferation and differentiation of spermatogonial stem cells (SSCs). These processes are tightly regulated by the SSC niche. Understanding the developmental mechanisms of SSCs is therefore critical for elucidating the basis of male fertility. Recent studies have shown that members of the G-protein-coupled receptor (GPCR) superfamily play key roles in ion and water balance in the epididymis, development of efferent ductules, blood-epididymal barrier formation, and sperm maturation. To investigate SSC development in humans, we performed microarray analysis to examine G-protein gene expression in single cells from six human testes. Our analysis revealed that genes such as LEPROT, LRRC15, LPAR1, SSR1, BMPR2, TNFRSF11B, TNFRSF10D, DDR2, SSR3, SIGMAR1, GRIA3, OGFRL1, GRIK2, TMEM87A, GPR108, TNFRSF1A, S1PR2, and VASN were down-regulated, while FLT1, ADGRG6, CSF1R, IL7R, ADGRL3, OR4N4, MMD, SIRPB1, OR5I1, PTGDR, MPL, and GPR107 were up-regulated. Single-cell transcriptomic and bioinformatic analyses were used to validate SSC-specific gene expression and assist in SSC isolation and sorting. Additionally, immunofluorescence labeling at different developmental stages provided insights into the spatial and temporal dynamics of spermatogonia. Our findings offer new insights into the molecular mechanisms governing human SSC development and provide a valuable foundation for advancing SSC-based fertility research and therapeutic applications.