Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington's disease.
In Huntington's disease (HD), cognitive symptoms and cellular dysfunction precede the onset of classical motor symptoms and neuronal death in the striatum and cortex by almost a decade. This suggests that the early cognitive deficits may be due to a cellular dysfunction rather than being a consequence of neuronal loss. Abnormalities in dendritic spines are described in HD patients and in HD animal models. Available evidence indicates that altered spine and synaptic plasticity could underlie the motor as well as cognitive symptoms in HD. However, the exact kinetics of spine alterations and plasticity in HD remain unknown. We used long-term two-photon imaging through a cranial window, to track individual dendritic spines in a mouse model of HD (R6/2) as the disease progressed. In vivo imaging over a period of 6 weeks revealed a steady decrease in the density and survival of dendritic spines on cortical neurons of R6/2 mice compared with control littermates. Interestingly, we also observed increased spine formation in R6/2 mice throughout the disease. However, the probability that newly formed spines stabilized and transformed into persistent spines was greatly reduced compared with controls. In cultured neurons we found that mutant huntingtin causes a loss, in particular of mature spines. Furthermore, in R6/2 mice, aggregates of mutant huntingtin associate with dendritic spines. Alterations in dendritic spine dynamics, survival, and density in R6/2 mice were evident before the onset of motor symptoms, suggesting that decreased stability of the cortical synaptic circuitry underlies the early symptoms in HD.
Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A10, 22184 Lund, Sweden.
Reena Prity
RP
Murmu
Wen
W
Li
Anthony
A
Holtmaat
Jia-Yi
JY
Li
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D018450:Disease Progression; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000473:pathology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D059906:Neuroimaging; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure*; D011597:Psychomotor Performance / Q000502:physiology; D013997:Time Factors
D000199:Actins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases