Abstract 146: Inducible Conditional Deletion of Dicer in Neural Progenitor Cells Induces Cognitive Impairment

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Abstract

Background: MicroRNAs regulate adult neurogenesis. Conditional deletion of Dicer in neural stem cells (NSCs) causes postnatal death. The functional role of Dicer in adult neurogenesis remains unknown. Using mice with inducible conditional knock-down of Dicer in adult NSCs, we investigated the effect of ablation of Dicer on neurogenesis and cognitive function.

Methods and Results: Young adult Ascl1-CreER:Dicerflox/flox mice (Dicer Cko, n= 32) were administered (i.p) with tamoxifen daily for 5 consecutive days and age matched wild-type litters (n= 30) were used as control. The mice were sacrificed at 2, 14 or 30 days after injection. Immunstaining was performed to detect phenotypes of subventricular zone (SVZ) cells. An array of cognitive tests including Morris Water Maze, odor-based novelty recognition, and sociability test were performed. Primary NPCs were isolated from the SVZ for vitro studies. Compared to control, Dicer CKo had 54% reduction of Dicer protein in NPCs. Cognitive tests showed that CKo spent 35% less time in the correct quadrant (p<0.05) of Morris Water Maze, significantly reduced time exploring new odor objects, 44 ±10% (p<0.05) in Cko animals compared with 77 ±10% in control, and significantly less time with other mice when they encountered a strange mouse during the sociability test (70 ± 9 vs 118 ±7 seconds, p<0.05). CKo significantly (p<0.05) reduced BrdU+ (16±2% vs 24±3%), and Ki67+ NPCs (25±3% vs 33±3%), doublecortin (DCX)+ neuroblasts (2± 0.6% vs 6± 1%), and Ng2+ oligodendrocyte progenitor cells (OPCs, 8±1% vs 12± 2%) in the SVZ. However, Dicer CKo animals exhibited a significant increase (p<0.05) of apoptotic NPCs (14±0.5% vs 10 ±0.3%). These in vivo findings were consistent with data from cultured NPCs. Dicer CKo also showed significant (p<0.05) reduction DCX+ neuroblasts in the rostral migratory stream and APC+ mature oligodendrocytes in the corpus callosum.

Conclusion: Our data demonstrated that inducible conditional ablation of Dicer in Ascl1 lineage NPCs impairs neurogenesis and oligodendrogenesis in adult SVZ niche and white matter, and induces cognitive impairment, indicating that Dicer in adult NPCs is essential for maintaining neurogenesis and oligodendrogenesis and is important for cognitive function.

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