There is now compelling evidence that the allocation of memory to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random and that instead specific mechanisms, such as increases in neuronal excitability and synaptic tagging and capture, determine the exact sites where memories are stored. We propose an integrated view of these processes, such that neuronal allocation, synaptic tagging and capture, spine clustering and metaplasticity reflect related aspects of memory allocation mechanisms. Importantly, the properties of these mechanisms suggest a set of rules that profoundly affect how memories are stored and recalled.
SUMMARY
Accumulation of tau is a critical event in several neurodegenerative
disorders, collectively known as tauopathies, which include Alzheimer’s
disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and
aggregates to form neurofibrillary tangles. The molecular mechanisms leading to
tau accumulation remain unclear and more needs to be done to elucidate them. Age
is a major risk factor for all tauopathies, suggesting that molecular changes
contributing to the aging process may facilitate tau accumulation and represent
common mechanisms across different tauopathies. Here, we use multiple animal
models and complementary genetic and pharmacological approaches to show that the
mammalian target of rapamycin (mTOR) regulates tau phosphorylation and
degradation. Specifically, we show that genetically increasing mTOR activity
elevates endogenous mouse tau levels and phosphorylation. Complementary to it,
we further demonstrate that pharmacologically reducing mTOR signaling with
rapamycin ameliorates tau pathology and the associated behavioral deficits in a
mouse model overexpressing mutant human tau. Mechanistically, we provide
compelling evidence that the association between mTOR and tau is linked to
GSK3β and autophagy function. In summary, we show that increasing mTOR
signaling facilitates tau pathology while reducing mTOR signaling ameliorates
tau pathology. Given the overwhelming evidence showing that reducing mTOR
signaling increases lifespan and health span, the data presented here have
profound clinical implications for aging and tauopathies and provide the
molecular basis for how aging may contribute to tau pathology. Additionally,
these results provide pre-clinical data indicating that reducing mTOR signaling
may be a valid therapeutic approach for tauopathies.
SummaryA period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX)-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.
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