Proteasome limits plasticity-related signaling to the nucleus in the hippocampus.

Proteolysis by the ubiquitin-proteasome pathway has pleiotropic effects on both induction and maintenance of long-term synaptic plasticity. In this study, we examined the effect of proteasome inhibition on signaling to the nucleus during late-phase long-term potentiation. When a subthreshold L-LTP induction protocol was used, proteasome inhibition led to a significant increase in phosphorylated CREB (pCREB) in the nucleus. Inhibitors of cAMP-dependent protein kinase/protein kinase A, extracellular signal-regulated kinase and cGMP-dependent protein kinase/protein kinase G all blocked the proteasome-inhibition-mediated increase in nuclear pCREB after subthreshold stimulation. These results lay the groundwork for understanding a novel role for the proteasome in limiting signaling to the nucleus in the absence of adequate synaptic stimulation.

Age-dependent changes in brain hydration and synaptic plasticity.

Aging in humans and animals is associated with gradual and variable changes in some cognitive functions, but what causes them and explains individual variations remains unclear. Hydration decreases with aging but whether dehydration contributes to cognitive dysfunction is not known. The brain hydration of aging mice was determined by colloidosmotic-pressure titration. Dehydration increased with age from ∼76 mmHg at 6 weeks to ∼105 mmHg at 40 weeks, or a progressive ∼10 percent loss of brain water but seemed to level off afterward. When we adjusted dehydration in hippocampal slices of <8-week-old mice to the levels seen in mice 40 weeks and older, their basal synaptic responses were amplified at all stimulus voltages tested, but induction of late-phase long-term potentiation was impaired. Our results document progressive brain dehydration with age in inbred mice to levels at which in vitro synaptic plasticity appears dysregulated. They also suggest that dehydration contributes to some of the changes in synaptic plasticity observed with aging, possibly due to adjustments in neuronal excitation mechanisms.

Proteasome regulates the mediators of cytoplasmic polyadenylation signaling during late-phase long-term potentiation.

The ubiquitin-proteasome pathway is essential for long-term synaptic plasticity, but its exact roles remain unclear. Previously we established that proteasome inhibition increased the early, induction part of late-phase long-term potentiation (L-LTP) but blocks the late, maintenance part. Our prior work also showed that the proteasome modulates components of the mammalian target of rapamycin pathway for translation. In this study, we tested the possible role of the proteasome in regulating the cytoplasmic polyadenylation signaling required for translation during L-LTP. We found that a polyadenylation inhibitor cordycepin diminishes the enhancement of early L-LTP mediated by proteasome inhibition. Furthermore, blocking Aurora-A kinase and calcium-calmodulin-dependent kinase II reduces the increase in early L-LTP brought about by proteasome inhibition. Our results suggest a link between polyadenylation-mediated translational control and protein degradation during induction of long-term synaptic plasticity.