GRIA3: proposal for a neuroimmune role linking infection, stress, chronic disorders and the activity of kynurenic acid

Glutamate receptors in the CNS sensitive to the analog AMPA regulate neuronal excitability and synaptic plasticity. AMPA receptors are usually hetero-tetramers and the human GRIA3 gene and GluA3 protein product have been implicated in various CNS abnormalities including epilepsy, multiple sclerosis, schizophrenia, and cognitive disorders. Although not generally found in the immune system, GRIA3 has recently been demonstrated in a highly specialized group of immune system cells–plasmacytoid dendritic cells (pDCs). These are among the first cells to be activated by infecting viruses and they express GRIA3 in the absence of other AMPA receptor subunits, suggesting a possible role for the subunit in those neuroimmune disorders. The potential for molecular interactions between pDCs and neurons or glia is discussed, with the implications for linking viral infections, pDC activation, and chronic diseases. With growing evidence that the tryptophan metabolite kynurenic acid—an AMPA antagonist—is involved with a similar range of disorders, its role in those links is also discussed.