Neurogenesis in the R6/1 transgenic mouse model of Huntington's disease: effects of environmental enrichment.
Previous work has demonstrated that the transgenic R6/1 mouse model of Huntington's disease has decreased proliferation of neural precursor cells (NPCs) in the dentate gyrus of the hippocampus. This study therefore examined the survival and differentiation of NPCs in presymptomatic and symptomatic R6/1 mice and the effects of environmental enrichment on these variables. Here it is demonstrated that the survival of bromodeoxyuridine-positive (BrdU+) NPCs in the dentate gyrus is decreased in the transgenic mice. In addition, the number of doublecortin-positive (DCX+) cells is greatly reduced in these mice, as is the total number of new mature neurons, while the proportion of BrdU+ cells differentiating into mature neurons was not significantly different between genotypes. Furthermore, the DCX+ cells in the R6/1 mice had smaller and irregular-shaped somas, shorter neurites, and migrated a shorter distance into the granular cell layer compared with wild-type mice. Older symptomatic mice housed in an enriched environment had an increased number of BrdU+ and DCX+ cells as well as longer neurites and increased migration of DCX+ cells. There was no significant difference between genotypes or environments in the number of BrdU+ cells in the subventricular zone. These results suggest that decreased neurogenesis might be responsible, in part, for the hippocampal deficits observed in these mice and that environmental enrichment produces morphological changes in newborn granule neurons in both wild-type and R6/1 mice, which could underlie some of the beneficial effects of enrichment.
Lazic
Stanley E
SE
Centre for Brain Repair, University of Cambridge, Cambridge CB2 2PY, UK. stan.lazic@cantab.net
Grote
Helen E
HE
Blakemore
Colin
C
Hannan
Anthony J
AJ
van Dellen
Anton
A
Phillips
Wendy
W
Barker
Roger A
RA
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D002552:Cerebral Ventricles / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004780:Environment, Controlled; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D007150:Immunohistochemistry; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity; D016501:Neurites / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology
C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases