Reversing Tics and Compulsions by Supercharging Striatal Microglia

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Minnesota
Investigators Name
Burton, Frank, PhD

We propose a “unified glutamate” hypothesis to reconcile disparate “neurogenic” and “immunogenic” origins of TS and OCD. Numerous studies suggest that neurogenic tics and compulsions may arise when corticostrial projection neurons deposit excessive striatal glutamate, and/or when postsynaptic neurons have defective glutamate response. Likewise, an immunogenic OCD/TTM mouse model (of defective bone-marrow derived brain microglia), and human PANDAS, suggest that immunogenic tics and compulsions may arise when inflamed striatal microglia deposit excessive perisynaptic glutamate, and/or when striatal microglia have defective glutamate reuptake. Hence tics and compulsions may arise from too much deposition, or too little reuptake, of excitatory glutamate. One therapeutic prediction of the unified glutamate hypothesis is that supercharging the number and activity of brain microglial cells should alleviate neurogenic TS+OCD. We will test this prediction on the neurogenic D1CT-7 “Ticcy” transgenic mouse, which exhibits tics and compulsions triggered by excessive corticostriatal glutamate deposition, by injecting them with mGM-CSF (mouse granulocyte macrophage-colony stimulating factor). By boosting, or “supercharging,” the number and/or activity of normal microglial cells and their regulated astrocytes in the mice’s brain and striatum, this treatment may increase perisynaptic glutamate reuptake to supranormal levels, eliminating the mice’s excess glutamate and hence alleviating their tics and compulsions. We will also test whether any observed change in the mice’s tic and/or compulsion severity caused by mGM-CSF treatment is associated with a corresponding change in their striatal microglial cell number and/or markers of microglial and astrocyte activation. This study will be the first to test the therapeutic potential of GM-CSF, presently clinically administered (as “sargramostim”) to cancer patients to alleviate tics and compulsions. Frank H. Burton, Ph.D. University of Minnesota, Minneapolis, MN Award: $75,000 Commentary: This investigator proposes that a “unified glutamate” hypothesis could explain how TS/OCD may be both neurological and immunological in nature. According to this theory, TS/OCD symptoms could occur when the level of a chemical called glutamate builds up in the brain tissue. This could happen when brain nerve cells or immune cells (microglial cells) either release too much glutamate into the brain tissue or absorb too little glutamate from the brain tissue. If this hypothesis is correct, then a drug called sargramostim which causes microglial cells to absorb more glutamate from the brain tissue, should alleviate TS and OCD symptoms. The investigator will test this hypothesis using specially bred mice that have TS/OCD-like symptoms. Tourette Association of America Inc. – Research Grant Award 2011-2012