The Effects of Inflammation on Dorsal Striatal Spiny Projection Neurons
Berger, Carissa Winland
Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of glutamate receptors. For example, the preferential trafficking of calcium-permeable (CP-AMPAR) versus impermeable AMPARs can result in disruptions of [Ca2+]i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca2+]i and L-type voltage-gated calcium channels (VGCCs) have been reported. Therefore, we sought to determine whether a proinflammatory environment alters AMPA-mediated [Ca2+]i through L-type VGCCs in dorsal striatal dopamine-2 and dopamine-1 expressing striatal spiny projection neurons (D2 and D1 SPNs). Mice expressing the calcium indicator protein GCaMP selectively in D2 or D1 SPNs were utilized for calcium imaging. Microglial activation was assessed by release of proinflammatory molecules and morphological changes. To induce inflammation, acute striatal slices were incubated with lipopolysaccharide (LPS) for two hours. Here we report that LPS potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA-mediated calcium fluorescence in D2 but not D1 SPNs. The remaining AMPA-stimulated [Ca2+]i was mediated by CP-AMPARs because the responses were completely blocked by a selective CP-AMPAR antagonist, philanthotoxin. In addition, LPS selectively decreased sensitivity AMPA-stimulated [Ca2+]i through CP-AMPARs, however we found that total CP-AMPARs were unchanged with LPS treatment. We did observe a role for GABA given that blockade of GABA receptors decreased AMPA-stimulated [Ca2+]i in LPS treated D2 SPNs. This suggests that the LPS mediated increase is dependent on VGCCs and GABA signaling. To further understand the role of VGCCs, we used isradipine, the highly specific L-type VGCC antagonist. Isradipine decreased AMPA-stimulated responses selectively in D2 SPNs after LPS treatment. This strongly implicates the L-type VGCCs in inflammatory conditions. We also examined NMDA-stimulated [Ca2+]i in SPNs and discovered an opposing effect of LPS treatment. Specifically, D2 SPNs demonstrated an increase in NMDA-stimulated [Ca2+]i whereas D1 SPNs demonstrated a decrease. Our findings suggest differential effects of a proinflammatory environment on D2 and D1 SPNs.
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