Multi-input Synapses, but Not LTP-Strengthened Synapses, Correlate with Hippocampal Memory Storage in Aged Mice.

Long-lasting changes at synapses enable memory storage in the brain. Although aging is associated with impaired memory formation, it is not known whether the synaptic underpinnings of memory storage differ with age. Using a training schedule that results in the same behavioral memory formation in young and aged mice, we examined synapse ultrastructure and molecular signaling in the hippocampus after contextual fear conditioning. Only in young, but not old mice, contextual fear memory formation was associated with synaptic changes that characterize well-known, long-term potentiation, a strengthening of existing synapses with one input. Instead, old-age memory was correlated with generation of multi-innervated dendritic spines (MISs), which are predominantly two-input synapses formed by the attraction of an additional excitatory, presynaptic terminal onto an existing synapse. Accordingly, a blocker used to inhibit MIS generation impaired contextual fear memory only in old mice. Our results reveal how the synaptic basis of hippocampal memory storage changes with age and suggest that these distinct memory-storing mechanisms may explain impaired updating in old age.

The Insoluble Protein Deposit (IPOD) in Yeast.

The appearance of protein aggregates is a hallmark of several pathologies including many neurodegenerative diseases. Mounting evidence suggests that the accumulation of misfolded proteins into inclusions is a secondary line of defense when the extent of protein misfolding exceeds the capacity of the Protein Quality Control System, which mediates refolding or degradation of misfolded species. Such exhaustion can occur during severe proteotoxic stress, the excessive occurrence of aggregation prone protein species, e.g., amyloids, or during ageing. However, the machinery that mediates recognition, recruitment and deposition of different types of misfolded proteins into specific deposition sites is only poorly understood. Since emerging principles of aggregate deposition appear evolutionarily conserved, yeast represents a powerful model to study basic mechanisms of recognition of different types of misfolded proteins, their recruitment to the respective deposition site and the molecular organization at the corresponding site. Yeast possesses at least three different aggregate deposition sites, one of which is a major deposition site for amyloid aggregates termed Insoluble PrOtein Deposit (IPOD). Due to the link between neurodegenerative disease and accumulation of amyloid aggregates, the IPOD is of particular interest when we aim to identify the molecular mechanisms that cells have evolved to counteract toxicity associated with the occurrence of amyloid aggregates. Here, we will review what is known about IPOD composition and the mechanisms of recognition and recruitment of amyloid aggregates to this site in yeast. Finally, we will briefly discuss the possible physiological role of aggregate deposition at the IPOD.

Age-dependent changes in autophosphorylation of alpha calcium/calmodulin dependent kinase II in hippocampus and amygdala after contextual fear conditioning.

The hippocampus and amygdala are essential brain regions responsible for contextual fear conditioning (CFC). The autophosphorylation of alpha calcium-calmodulin kinase II (αCaMKII) at threonine-286 (T286) is a critical step implicated in long-term potentiation (LTP), learning and memory. However, the changes in αCaMKII levels with aging and training in associated brain regions are not fully understood. Here, we studied how aging and training affect the levels of phosphorylated (T286) and proportion of phosphorylated:total αCaMKII in the hippocampus and amygdala. Young and aged mice, naïve (untrained) and trained in CFC, were analysed by immunohistochemistry for the levels of total and phosphorylated αCaMKII in the hippocampus and amygdala. We found that two hours after CFC training, young mice exhibited a higher level of phosphorylated and increased ratio of phosphorylated:total αCaMKII in hippocampal CA3 stratum radiatum. Furthermore, aged untrained mice showed a higher ratio of phosphorylated:total αCaMKII in the CA3 region of the hippocampus when compared to the young untrained group. No effect of training or aging were seen in the central, lateral and basolateral amygdala regions, for both phosphorylated and ratio of phosphorylated:total αCaMKII. These results show that aging impairs the training-induced upregulation of autophosphorylated (T286) αCaMKII in the CA3 stratum radiatum of the hippocampus. This indicates that distinct age-related mechanisms underlie CFC that may rely more heavily on NMDA receptor-dependent plasticity in young age.