Hypothesis of MDD: excess CNS glutamate may contribute to excess Th1- response promoting neuroprotective microglia. Peripheral resting T lymphocytes constitutively express mGluR5. Activated T lymphocytes, but not resting T lymphocytes, can cross the BBB. In the animal models, the interaction between TCR of activated T lymphocytes and their cognate antigen presenting cells downregulates mGluR5 and induces mGluR1 expressions. Experimental data suggest that excess glutamate can bind to lymphocytic mGluR1 receptors, promoting production of Th1 cytokines. Hypothesis: In some MDD patients, parallel to experimental data, binding of excess CNS glutamate to induced lymphocytic mGluR1 receptors may contribute to an excess Th1 response, including IFN-γ. We further hypothesize that IFN-γ in a small quantity, similar to its in vitro effects on microglia, may induce microglial expression of MHC-II and EAAT-2, allowing microglia to serve as cognate antigen presenting cells and to provide glutamate reuptake function, thereby transforming harmful microglia into neuroprotective phenotype that participate in eliminating excess extracellular glutamate and reducing its excitotoxicity. Therefore, we hypothesize that excess Th1 response in some MDD patients is a double-edged sword; promoting harmful inflammation and serving as a beneficial counter-regulatory mechanism that may limit excess glutamate-related neuroexcitotoxicity? AMPA, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)-propanoic acid; APC, antigen presenting cell; BBB, blood–brain barrier; CNS, central nervous system, EAAT, excitatory amino acid transporter; IDO, indoleamine-2,3-dioxygenase; IFN-γ, interferon gamma; IL, interleukin; KMO, kynurenine 3-monooxygenase; mGluR1/5, metabotropic glutamate receptors 1 and 5; MHC II, major histocompatibility complex class 2; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NR1, glycine site; QA, quinolinic acid; TCR, T-cell receptor; Th, T-helper; TNF-α, tumor necrosis factor alpha.