154. Neurotrophin and indoleamine/tryptophan 2,3-dioxygenase regulation in murine organotypic striatal slice cultures

The striatum is a subcortical region of the forebrain that is rich in spiny GABAergic neurons (90–95%). These neurons receive afferent signals from the frontal cortex and substantia nigra and transmit inhibitory signals to key regions that regulate motivation and reward, linking striatal function to several mood disorders including major depression. We have previously shown that reduced mRNA expression of insulin-like growth factor-I (Igf1) and brain-derived neurotrophic growth factor (Bdnf), coupled with elevated indoleamine-2,3-dioxygenase-1 (Ido1), are linked to development of depression-like behaviors. Here we used organotypic striatal slice cultures (OSSCs) to determine if inflammatory signals (interferon (IFN)-gamma and LPS) and a stress hormone (dexamethasone) are responsible for the differential regulation of these pathways. Following treatment, OSSCs were used to quantify Ido1, Ido2, tryptophan-2,3-dioxygenase (Tdo2), Igf1 and Bdnf mRNA. IFNγ was the most potent inducer of Ido1, followed poorly by LPS. In contrast, LPS and IFNγ equally induced Ido2. IFNγ reduced both Igf1 and Bdnf expression. Dexamethasone also reduced Igf1 and Bdnf. Dexamethasone induced Tdo2, but did not induce either Ido1 or Ido2 expression. These data establish that both inflammatory signals and dexamethasone reduce neurotrophin expression but increase tryptophan metabolism. More importantly, the results establish that three different kynurenine generating dioxygenases are expressed within the striatum, all of which are differentially regulated by IFNγ, LPS and glucocorticoids. (Supported by MH083767 to RHM and SUB-UT-00000712 to KWK).