Inflammation alters AMPA‐stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons

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 AMPARs. The preferential trafficking of calcium‐permeable 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, this study sought to determine whether a proinflammatory environment alters AMPA‐stimulated [Ca2+]i through calcium‐permeable AMPARs and/or L‐type VGCCs in dopamine‐2‐ and dopamine‐1‐expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum. Mice expressing the calcium indicator protein, GCaMP in D2 or D1 SPNs, were utilized for calcium imaging. Microglial activation was assessed by morphology analyses. To induce inflammation, acute mouse striatal slices were incubated with lipopolysaccharide (LPS). Here we report that LPS treatment potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA‐stimulated calcium fluorescence in D2 but not D1 SPNs. The remaining agonist‐induced [Ca2+]i was mediated by calcium‐permeable AMPARs because the responses were completely blocked by a selective calcium‐permeable AMPAR antagonist. We used isradipine, the highly selective L‐type VGCC antagonist to determine the role of L‐type VGCCs in SPNs treated with LPS. Isradipine decreased AMPA‐stimulated responses selectively in D2 SPNs after LPS treatment. Our findings suggest that dorsal striatal D2 SPNs are specifically targeted in proinflammatory conditions and that L‐type VGCCs and calcium‐permeable AMPARs are important mediators of this effect. Representative schematic of a corticostriatal slice illustrating the experimental procedure and the main finding that LPS treatment increases AMPA‐stimulated calcium responses in indirect pathway striatal projection neurons. The red line indicates the average of all responding cells.