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Abstract Details

Characterization of Novel Mouse Models of Microglial Conditional Knockout of L-type Calcium Channel Cav1.2 and Cav1.3 Subtypes
Aging, Dementia, and Behavioral Neurology
P3 - Poster Session 3 (5:00 PM-6:00 PM)
12-004

To characterize brain immune response and behavioral performance of two novel mouse models of microglia-specific L-type calcium channel (LTCC) knockout.

LTCC antagonists act at Cav1.2 and Cav1.3 and have been associated with reduced risk of dementia in humans, but the mechanism of this effect remains unclear. We have previously observed that LTCC antagonists reduce microglial transition to a pro-inflammatory state. We posit that LTCC antagonists act at microglial Cav1.2 or Cav1.3 to exert their neuroprotective effect by blocking the neurotoxic effects of pro-inflammatory microglia.

To test the hypothesis that microglial Cav1.2 or Cav1.3 controls microglia phenotype, we generated Cav1.2 and Cav1.3 microglia-specific conditional knockout (CKO) mice. We crossed CX3CR1-CreERT2 mice with Cav1.2fl/fl or Cav1.3flexGFP mice to generate Cav1.2 CKO (CKO2) and Cav1.3 CKO (CKO3) mice, respectively. We assessed the effects of each CKO on mouse behavior in tests for locomotion (open field), recognition memory (novel object recognition), and spatial learning and memory (Barnes maze). We also measured inflammatory gene expression using qPCR. For each test, we compared each CKO to the corresponding floxed control mouse and all groups to CX3CR1-CreERT2 controls.
In the Barnes maze, Cav1.2fl/fl and CKO2 mice had a significantly increased latency to target during training compared to Cre-only mice, suggesting impaired spatial learning in the former genotypes. There were significant changes in inflammatory gene expression in the brains of Cav1.3flexGFP and CKO3 mice including an increase in TGF-β in CKO3, suggesting increased anti-inflammatory signaling in these mice.
Preliminary results reveal an anti-inflammatory effect of microglial Cav1.3 knockout and spatial learning impairment in microglial Cav1.2 knockout. These findings indicate that LTCC antagonist action at microglial Cav1.3 may be the source of the neuroprotective effect of these drugs. Further work will include immunohistochemical staining to determine the efficacy of each microglial conditional knockout.
Authors/Disclosures
Rachael K. Cundey
PRESENTER 		Ms. Cundey has nothing to disclose.
Brinda Palliyana Ms. Palliyana has nothing to disclose.
gwenn smith, PhD Dr. smith has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Assocation for Geriatric Psychiatry.
Sarah C. Hopp, PhD The institution of Dr. Hopp has received research support from NIH. Dr. Hopp has received personal compensation in the range of $0-$499 for serving as a study section reviewer with NIH. Dr. Hopp has a non-compensated relationship as a executive committee member with Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment that is relevant to AAN interests or activities.