Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories.

Our memories are the records of the experiences we gain in our everyday life. Over time, they slowly transform from an initially unstable state into a long-lasting form. Many studies have been investigating from different aspects how a memory could persist for sometimes up to decades. In this review, we highlight three of the greatly addressed mechanisms that play a central role for a given memory to endure: the allocation of the memory to a given neuronal population and what brain areas are recruited for its storage; the structural changes that underlie memory persistence; and finally the epigenetic control of gene expression that might regulate and support memory perseverance. Examining such key properties of a memory is essential towards a finer understanding of its capacity to last.

The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity.

Over the last two decades, the identification of missense mutations in the α-synuclein (α-Syn) gene SNCA in families with inherited Parkinson disease (PD) has reinforced the central role of α-Syn in PD pathogenesis. Recently, a new missense mutation (H50Q) in α-Syn was described in patients with a familial form of PD and dementia. Here we investigated the effects of this novel mutation on the biophysical properties of α-Syn and the consequences for its cellular function. We found that the H50Q mutation affected neither the structure of free or membrane-bound α-Syn monomer, its interaction with metals, nor its capacity to be phosphorylated in vitro. However, compared with the wild-type (WT) protein, the H50Q mutation accelerated α-Syn fibrillization in vitro. In cell-based models, H50Q mutation did not affect α-Syn subcellular localization or its ability to be phosphorylated by PLK2 and GRK6. Interestingly, H50Q increased α-Syn secretion from SHSY5Y cells into culture medium and induced more mitochondrial fragmentation in hippocampal neurons. Although the transient overexpression of WT or H50Q did not induce toxicity, both species induced significant cell death when added to the culture medium of hippocampal neurons. Strikingly, H50Q exhibited more toxicity, suggesting that the H50Q-related enhancement of α-Syn aggregation and secretion may play a role in the extracellular toxicity of this mutant. Together, our results provide novel insight into the mechanism by which this newly described PD-associated mutation may contribute to the pathogenesis of PD and related disorders.

Reactivation of Recall-Induced Neurons in the Infralimbic Cortex and the Basolateral Amygdala After Remote Fear Memory Attenuation.

Whether the attenuation of traumatic memories is mediated through the suppression of the original memory trace of fear by a new memory trace of safety, or through an updating of the original fear trace towards safety has been a long-standing question at the interface of neuroscience and psychology. This matter is of particular importance for remote fear memories as they lie at the core of stress- and anxiety-related disorders. Recently, we have found that in the dentate gyrus, the effective attenuation of remote fear memories is accompanied by a reactivation of memory recall-induced neurons and that the continued activity of these neurons is critical for fear reduction. However, whether this also applies to other brain areas implicated in the storage of remote fear memories remains to be determined. Here, we show-by cellular compartment analysis of temporal activity using fluorescence in situ hybridization-that such reactivation also occurs in the basolateral amygdala and the infralimbic cortex, two brain areas known to be involved in fear memory attenuation. These results provide further experimental support for effective traumatic memory attenuation likely being mediated by an updating of the original fear trace towards safety.

Reactivation of recall-induced neurons contributes to remote fear memory attenuation.

Whether fear attenuation is mediated by inhibition of the original memory trace of fear with a new memory trace of safety or by updating of the original fear trace toward safety has been a long-standing question in neuroscience and psychology alike. In particular, which of the two scenarios underlies the attenuation of remote (month-old) fear memories is completely unknown, despite the impetus to better understand this process against the backdrop of enduring traumata. We found-chemogenetically and in an engram-specific manner-that effective remote fear attenuation is accompanied by the reactivation of memory recall-induced neurons in the dentate gyrus and that the continued activity of these neurons is critical for fear reduction. This suggests that the original memory trace of fear actively contributes to remote fear attenuation.

Ca2+-Calmodulin regulates SNARE assembly and spontaneous neurotransmitter release via v-ATPase subunit V0a1.

Most chemical neurotransmission occurs through Ca(2+)-dependent evoked or spontaneous vesicle exocytosis. In both cases, Ca(2+) sensing is thought to occur shortly before exocytosis. In this paper, we provide evidence that the Ca(2+) dependence of spontaneous vesicle release may partly result from an earlier requirement of Ca(2+) for the assembly of soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complexes. We show that the neuronal vacuolar-type H(+)-adenosine triphosphatase V0 subunit a1 (V100) can regulate the formation of SNARE complexes in a Ca(2+)-Calmodulin (CaM)-dependent manner. Ca(2+)-CaM regulation of V100 is not required for vesicle acidification. Specific disruption of the Ca(2+)-dependent regulation of V100 by CaM led to a >90% loss of spontaneous release but only had a mild effect on evoked release at Drosophila melanogaster embryo neuromuscular junctions. Our data suggest that Ca(2+)-CaM regulation of V100 may control SNARE complex assembly for a subset of synaptic vesicles that sustain spontaneous release.