Abstract
Decreased rRNA synthesis and nucleolar disruption, known as nucleolar stress, are primary signs of cellular stress associated with aging and neurodegenerative disorders. Silencing of rDNA occurs during early stages of Alzheimer's disease (AD) and may play a role in dementia. Moreover, aberrant regulation of the protein synthesis machinery is present in the brain of suicide victims and implicates the epigenetic modulation of rRNA. Recently, we developed unique mouse models characterized by nucleolar stress in neurons. We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3, and dentate gyrus (DG). Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice show normal performance in the Morris water maze and in other behavioral tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription. This phenomenon is accompanied by aberrant synaptic plasticity. By the analysis of nucleolar function and integrity, we find that the synthesis of rRNA is later restored. Gene expression profiling shows that 36 transcripts are differentially expressed in comparison to the control group in absence of neurodegeneration. Additionally, we observe a significant enrichment of the putative serum response factor (SRF) binding sites in the promoters of the genes with changed expression, indicating potential adaptive mechanisms mediated by the mitogen-activated protein kinase pathway. In the DG a neurogenetic response might compensate the initial molecular deficits. These results underscore the role of nucleolar stress in neuronal homeostasis and open a new ground for therapeutic strategies aiming at preserving neuronal function.
Highlights
Protein synthesis is essential in the consolidation of long-term memory by long-lasting changes of synapses (Cajigas et al, 2010)
GAPDH mRNA used as a control does not change (Figure 1A). rRNA transcription monitored by in situ hybridization detecting the nascent 47S pre-rRNA in hippocampal sections was strongly inhibited in the CA1 and dentate gyrus (DG) 1 month after tamoxifen was given confirming our previous data (Parlato et al, 2008) (Figure 1B)
Because we have recently reported that loss of TIF-IA leads to downregulation of mammalian target of rapamycin (mTOR) activity and neurodegeneration of dopaminergic neurons (Rieker et al, 2011), we have analyzed mTOR activity in CA1 and DG of TIF-IACaMKCreERT2 mutants and controls 1 and 8 months after tamoxifen to establish how this pathway responds to nucleolar stress in hippocampal neurons
Summary
Protein synthesis is essential in the consolidation of long-term memory by long-lasting changes of synapses (Cajigas et al, 2010). Neuronal stimulation and prolonged neuronal activity increase protein synthesis by controlling nucleolar number and/or by regulating processing and maturation of rRNA (Jordan et al, 2007). In line with a crucial role in learning and memory, rRNA transcription is down-regulated during ageing in CA1 and dentate gyrus (DG) hippocampal areas in CA3 it is increased to compensate the functional loss in DG and CA1. CA1 and DG are especially vulnerable to brain injury and Alzheimer’s disease (AD), supporting the connection between neuronal activity, metabolism, and functional deficits in aged hippocampal neurons (Garcia Moreno et al, 1997). RRNA transcription is decreased in hippocampal neurons after alcohol consumption and deprivation in rats and it is associated with memory impairment (Garcia-Moreno et al, 2001). A better understanding of the cellular and molecular strategies adopted to counteract nucleolar stress could pave the way to neuroprotective strategies preserving neuronal function
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