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

Abstract

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, the present 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.

MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia

“…Likewise, roundness (the inverse of the Feret ratio; where a circle has a roundness value of 0.5), was 0.49 after vehicle exposure compared with 0.62 in A53T-exposed microglia ( P ≤ 0.0001; Figure 2B ). Taken together, these measurements demonstrated that A53T exposure led to a shift in microglia morphology from a rod-like shape to a more amoeboid shape, which is often associated with a rise in phagocytosis (Perez-Pouchoulen et al, 2015 ; Winland et al, 2017 ; Dubbelaar et al, 2018 ).…”

“…Student's t -test was used to analyze data from qRT-PCR, ELISAs, morphological measurements, nuclear fluorescent intensity, and total fluorescent intensity unless otherwise stated. Data points shown represent individual cells for morphology and fluorescent intensity and values were not averaged per well since wells are not always homogenous in primary cultures (Allen et al, 2016 ; Hoenen et al, 2016 ; De Biase et al, 2017 ; Winland et al, 2017 ; Abdolhoseini et al, 2019 ; Svoboda et al, 2019 ). Significance threshold was set at P ≤ 0.05.…”

Apoptosis-associated speck-like protein containing a CARD-mediated release of matrix metalloproteinase 10 stimulates a change in microglia phenotype

“…Exposure to the inflammasome adaptor protein ASC can induce morphological changes in microglia Since it is well established that microglia respond to their environment by adopting an ameboid shape in the presence of inflammatory stimuli such as LPS, we wanted to evaluate the impact of enriched ASC aggregates (ASCspecks) on microglia morphology (Torres-Platas et al, De Biase et al, 2017;Winland et al, 2017). To that end we examined the consequences of ASC-specks treatment on microglial shape 12 h post-treatment.…”

Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice

“…Synaptic plasticity in iSPN has been shown to be calcium-dependent (Trusel et al, 2015). Inflammation increases AMPA responses through Ca 2+ -permeable AMPA receptors and voltage-gated calcium channels specifically in iSPNs of the dorsal striatum (Winland et al, 2017). Since DA lesion triggers an inflammatory response (Cicchetti et al, 2002), it will be important to examine its contribution to the altered responsiveness of iSPNs.…”