The microtubule binding protein tau is implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) with Parkinsonism caused by diverse mutations in the tau gene. Hyperphosphorylation of tau is considered crucial in the age-related formation of neurofibrillary tangles (NFTs) correlating well with neurotoxicity and cognitive defects. Transgenic mice expressing FTD mutant tau-P301L recapitulate the human pathology with progressive neuronal impairment and accumulation of NFT. Here, we studied tau-P301L mice for parameters of learning and memory at a young age, before hyperphosphorylation and tauopathy were apparent. Unexpectedly, in young tau-P301L mice, increased long-term potentiation in the dentate gyrus was observed in parallel with improved cognitive performance in object recognition tests. Neither tau phosphorylation, neurogenesis, nor other morphological parameters that were analyzed could account for these cognitive changes. The data demonstrate that learning and memory processes in the hippocampus of young tau-P301L mice are not impaired and actually improved in the absence of marked phosphorylation of human tau. We conclude that protein tau plays an important beneficial role in normal neuronal processes of hippocampal memory, and conversely, that not tau mutations per se, but the ensuing hyperphosphorylation must be critical for cognitive decline in tauopathies.
BackgroundThe stress hormone corticosterone has the ability both to enhance and suppress synaptic plasticity and learning and memory processes. However, until today there is very little known about the molecular mechanism that underlies the bidirectional effects of stress and corticosteroid hormones on synaptic efficacy and learning and memory processes. In this study we investigate the relationship between corticosterone and AMPA receptors which play a critical role in activity-dependent plasticity and hippocampal-dependent learning.Methodology/Principal FindingsUsing immunocytochemistry and live cell imaging techniques we show that corticosterone selectively increases surface expression of the AMPAR subunit GluR2 in primary hippocampal cultures via a glucocorticoid receptor and protein synthesis dependent mechanism. In agreement, we report that corticosterone also dramatically increases the fraction of surface expressed GluR2 that undergo lateral diffusion. Furthermore, our data indicate that corticosterone facilitates NMDAR-invoked endocytosis of both synaptic and extra-synaptic GluR2 under conditions that weaken synaptic transmission.Conclusion/SignificanceOur results reveal that corticosterone increases mobile GluR2 containing AMPARs. The enhanced lateral diffusion properties can both facilitate the recruitment of AMPARs but under appropriate conditions facilitate the loss of synaptic AMPARs (LTD). These actions may underlie both the facilitating and suppressive effects of corticosteroid hormones on synaptic plasticity and learning and memory and suggest that these hormones accentuate synaptic efficacy.
Stress facilitates memory formation, but only when the stressor is closely linked to the learning context. These effects are, at least in part, mediated by corticosteroid hormones. Here we demonstrate that corticosterone rapidly facilitates synaptic potentiation in the mouse hippocampal CA1 area when high levels of the hormone and high-frequency stimulation coincide in time, but not when corticosterone is given either before or after repetitive stimulation. This effect could not be blocked by antagonists of the mineralocorticoid receptor and glucocorticoid receptor (spironolactone and RU 38486, respectively). These data provide a biological substrate for the important behavioral observation that stress and corticosteroid hormones can facilitate learning and memory processes.Corticosteroid hormones (corticosterone in most rodents, cortisol in humans) are released in high amounts from the adrenal gland after exposure to stress; hormone levels rise within 5-10 min, peak ∼30 min, and normalize within 60-90 min after stress exposure (de Kloet et al. 2005). Corticosterone enters the brain and binds to intracellular receptors, which act as transcription factors; recently, rapid non-genomic effects have also been reported in brain, not only for corticosterone (Di et al. 2003;Kruk et al. 2004;, but also for other steroid hormones (for review, see Losel et al. 2003).Corticosteroid hormones are key factors in the effects of aversive and emotional situations on learning and memory processes, both in humans and animals (Lupien and McEwen 1997). Stress and elevated corticosteroid hormone levels hamper the retrieval of previously learned information as well as impair the acquisition and storage of additional information (Krugers et al. 1997;de Quervain et al. 1998;Roozendaal et al. 2003;Kuhlmann et al. 2005). Yet, stress and corticosterone are known to facilitate memory formation when they form an intrinsic part of the learning context or are given in close conjunction to a learning test (Sandi and Rose 1994;Roozendaal and McGaugh 1996;Oitzl et al. 2001). The neurobiological substrate for this behavioral observation, however, is not very clear. Thus, hippocampal synaptic potentiation-currently the best documented substrate for learning and memory formation involving the hippocampus (Bliss and Collingridge 1993)-was consistently found to be impaired instead of facilitated by earlier applied stress or high levels of corticosterone (Pavlides et al. 1996;Xu et al. 1997;Kim and Diamond 2002). It has been postulated that stress or corticosterone may prime synaptic circuits such that the threshold for synaptic potentiation induced 1-2 h later is enhanced (Kim and Yoon 1998). We hypothesized that synaptic potentiation will be facilitated when corticosterone and induction of potentiation coincide in time, as is likely to occur during stressful learning conditions, rather than being events that are separated in time.Male C57/black6 mice (∼6 wk of age) were obtained from Harlan CPB. Upon arrival the animals were individually housed with ...
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