Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a “master switch” regulating synaptic gain in neuronal networks

Abstract

Arendt T, Bullmann T. Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a "master switch" regulating synaptic gain in neuronal networks. Am J Physiol Regul Integr Comp Physiol 305: R478 -R489, 2013. First published July 13, 2013 doi:10.1152/ajpregu.00117.2013.-The present paper provides an overview of adaptive changes in brain structure and learning abilities during hibernation as a behavioral strategy used by several mammalian species to minimize energy expenditure under current or anticipated inhospitable environmental conditions. One cellular mechanism that contributes to the regulated suppression of metabolism and thermogenesis during hibernation is reversible phosphorylation of enzymes and proteins, which limits rates of flux through metabolic pathways. Reversible phosphorylation during hibernation also affects synaptic membrane proteins, a process known to be involved in synaptic plasticity. This mechanism of reversible protein phosphorylation also affects the microtubule-associated protein tau, thereby generating a condition that in the adult human brain is associated with aggregation of tau protein to paired helical filaments (PHFs), as observed in Alzheimer's disease. Here, we put forward the concept that phosphorylation of tau is a neuroprotective mechanism to escape NMDA-mediated hyperexcitability of neurons that would otherwise occur during slow gradual cooling of the brain. Phosphorylation of tau and its subsequent targeting to subsynaptic sites might, thus, work as a kind of "master switch," regulating NMDA receptor-mediated synaptic gain in a wide array of neuronal networks, thereby enabling entry into torpor. If this condition lasts too long, however, it may eventually turn into a pathological trigger, driving a cascade of events leading to neurodegeneration, as in Alzheimer's disease or other "tauopathies".Alzheimer's disease; neurodegeneration; neuroprotection; neuronal plasticity; protein phosphorylation; tauopathies Seasonal Brain Plasticity Might Be a Widespread PhenomenonANIMALS LIVING IN ENVIRONMENTS with daily or seasonal rhythms have developed different strategies to coordinate endogenous processes with ambient conditions. To optimize their energy balance under conditions of restricted availability of food and increased costs for temperature regulation, animals can either reduce the expense for foraging or the need of foraging (96). The expense for foraging can be reduced by food storing or escaping a cold climate by migration. Alternatively, hibernation is a powerful strategy to reduce the metabolic costs of daily activity. All of these aforementioned strategies to optimize energy expenditure are associated with plastic adaptive changes both at the level of behavior and brain structure.The seasonal modulation of food-storing behavior (33,177,178,182) or migration (17) in birds has been shown to require special spatial learning abilities, which are paralleled by seasonal changes in neuronal structure. These cyclic changes in size and mo...

Tau phosphorylation‐associated spine regression does not impair hippocampal‐dependent memory in hibernating golden hamsters

“…We assume chronic exposure to cold environment might actually increase performance as it has been reported before (review: Palinkas, ). In summary, the cold temperature during hibernation does not affect spatial memory, which is consistent with the previous finding that after consolidation memory is more resistant (Andjus et al, ) than immediately after acquisition (Moser and Andersen, ) (review: Andersen and Moser, ; Arendt and Bullmann, ).…”

Metabolic Flexibility: Hibernation, Torpor, and Estivation

“…This process is likely mediated by hyperphosphorylation of tau, a microtubule associated protein, but prolonged regression may lead to neuropathies, so arousal may serve to reverse temporarily the tau hyperphosphorylation and synaptic regression, minimizing neuronal damage in hibernators (reviewed in ref. 7).…”

Terminal hypothermic Tau.P301L mice have increased Tau phosphorylation independently of glycogen synthase kinase 3α/β

“…Phosphorylation of Tau is known to depend on body temperature, physiologically in hibernating mammals, and as a well-known complication of anesthesia (Arendt et al, 2003;Planel et al, 2007;Su et al, 2008;Run et al, 2009;Tan et al, 2010;Menuet et al, 2011bMenuet et al, , 2012Arendt & Bullmann, 2013). Preliminary measurements of body temperature in terminal Tau.P301L mice with a normal GSK3 background, or deficient in either GSK3 isozyme, revealed variable lowered core body temperatures in the terminal stages, ranging from nearly normal to as low as 22°C.…”

“…Interestingly, our observations of the relationships between hypothermia in terminal Tau.P301L mice and the phosphorylation of Tau paralleled the phosphorylation of Tau in certain hibernating species. Most spectacular are hibernating arctic ground squirrels, which accumulate, in their central neurons, very high levels of phosphorylated tau that are fully reversible upon arousal (Arendt et al, 2003;Su et al, 2008;Stieler et al, 2011;Arendt & Bullmann, 2013). Simi- larly, in hypothermic terminal Tau.P301L mice, we found that raising their body temperature above 32°C reversed, although not completely, the hyperphosphorylation of Tau.P301L and, to a lesser extent, the level of insoluble Tau aggregates.…”

“…Physiologically, hibernating animals develop severe hyperphosphorylation of Tau, which is fully reversed upon arousal (Arendt et al, 2003;H€ artig et al, 2007;Stieler et al, 2011;Arendt & Bullmann, 2013). The physiological importance remains speculative; the mechanism concerns the temperature sensitivity of phosphatases relative to kinases (Su et al, 2008).…”