Abstract
Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG) regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β) levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light–dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes.
Highlights
GSK3 is a kinase present in most tissues and is abundant in the brain [1]
Increased GSK3 activity is believed to play a key role in the pathogenesis of chronic metabolic disorders like type-II diabetes [3], as well as of CNS conditions such as bipolar mood disorder [4], schizophrenia [5], diseases like Huntington’s disease [6], frontotemporal dementia with parkinsonism linked to chromosome 17 [7] and Alzheimer disease [8]
Western blot determination of the phosphorylated form of glycogen synthase kinase-3b (GSK3b) revealed an increase in the ratio phosphorylated/unphosphorylated forms in ventral area compared with dorsal area in wild-type mice (Figure 1)
Summary
GSK3 is a kinase present in most tissues and is abundant in the brain [1]. Increased GSK3 activity is believed to play a key role in the pathogenesis of chronic metabolic disorders like type-II diabetes [3], as well as of CNS conditions such as bipolar mood disorder [4], schizophrenia [5], diseases like Huntington’s disease [6], frontotemporal dementia with parkinsonism linked to chromosome 17 [7] and Alzheimer disease [8]. With regard to GSK3 and neurodegeneration, increased GSK3 activity has been reported to result in neuronal apoptosis and GSK3 inhibitors have been shown to exert antiapoptotic and neuroprotective effects in many different cell and mouse models [9,10,11]. Potent and specific GSK3 inhibitors are currently under development [12,13,14]
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