glutaminergic hypofunction as NRG1 hypofunction leads to schizophrenia-pattern behavior in mice; likely due in part to reduced NMDA signaling via Src suppression. The role of synaptic pruning Various neurotrophic factors dysregulate in schizophrenia and other mental illnesses, namely BDNF; expression of which is lowered in schizophrenia as well as in major depression and bipolar disorder. BDNF regulates in an AMPA-dependent mechanism - AMPA and BDNF alike are critical mediators of growth cone survival. NGF, another neurotrophin involved in maintenance of synaptic plasticity is similarly seen in deficit. Dopaminergic excess, classically understood to result in schizophrenia, puts oxidative load on neurons; leading to inflammatory response and microglia activation. Similarly, toxoplasmosis infection in the CNS (positively correlated to schizophrenia) activates inflammatory cascades, also leading to microglion activation. The lipoxygenase-5 inhibitor minocycline has been seen to be marginally effective in halting schizophrenia progression. One of such inflammatory cascades' downstream transcriptional target, NF-κB, is observed to have altered expression in schizophrenia. In addition, CB2 is one of the most widely distributed glial cell-expressed receptors, downregulation of this inhibitory receptor may increase global synaptic pruning activity. While difference in expression or distribution is observed, when the CB2 receptor is knocked out in mice, schizophreniform behaviors manifest. This may deregulate synaptic pruning processes in a tachyphlaxis mechanism wherein immediate excess CB2 activity leads to phosphorylation of the receptor via GIRK, resultant in b-arrestin-dependent internalization and subsequent trafficking to the proteasome for degradation. The role of endogenous antagonists Alterations in production of endogenous NMDA antagonists such as agmatine and kynurenic acid have been shown in schizophrenia. Deficit in NMDA activity produces psychotomimetic effects, though it remains to be seen if the blockade of NMDA via these agents is causative or actually mimetic of patterns resultant from monoaminergic disruption. AMPA, the most widely distributed receptor in the brain, mediates long term potentiation via activity-dependent modulation of AMPA density. GluR1 subunit-containing AMPA receptors are Ca2+ permeable while GluR2/3 subunit-positive receptors are nearly impermeable to calcium ions. In the regulated pathway, GluR1 dimers populate the synapse at a rate proportional to NMDA-ergic Ca2+ influx. In the constitutative pathway, GluR2/3 dimers populate the synapse at a steady state. This forms a positive feedback loop, where a small trigger impulse degating NMDA from Mg2+ pore blockade results in calcium influx, this calcium influx then triggers trafficking of GluR1-containing(Ca2+ permeable) subunits to the PSD, such trafficking of GluR1-positive AMPA to the postsynaptic neuron