β淀粉样蛋白寡聚体毒性环境下Bryostatin-1对神经突触活性的影响和潜在机制

在原代海马神经元上建立通过外加Aβ寡聚体所导致的突触毒性模型,并使用蛋白印迹、激酶活性、激光共聚焦显微成像和电生理等技术检测PKC激酶的非选择性激动剂Bryostatin-1是否可以保护Aβ寡聚体导致的突触毒性。结果显示,在Aβ毒性模型中,Bryostatin-1可以改善树突棘的形态,并促进树突棘成熟。此外,电生理结果显示Bryostatin-1可以显著改善突触后的微型兴奋性突触后电流频率,AMPA受体与NMDA受体的比例并没有发生显著改变。蛋白印迹结果显示Bryostatin-1可以上调突触生物标记物水平。蛋白印迹试验结果表明,Bryostatin-1可以上调mTOR-S6K1信号通路的活性。通过在神经元中转染GFP-RFP-LC3质粒并进行激光共聚焦显微观察,结果提示Aβ寡聚体可以抑制神经元内自噬通量,而Bryostatin-1可以提高被Aβ寡聚体所抑制的自噬通量。结果提示,Bryostatin-1激活mTOR-S6K1信号通路,并随后调节细胞自噬功能可能是其在Aβ寡聚体毒性环境下保护神经元突触功能的分子机制。

UNC-64 and RIC-4,the plasma membrane-associated SNAREs syntaxin and SNAP-25,regulate fat storage in nematode Caenorhabditis elegans

Objective To investigate whether genes required for synaptogenesis and synaptic function are also involved in fat storage control in Caenorhabditis elegans. Methods Fat storage was examined in mutants of genes affecting the synaptogenesis and synaptic function. In addition, the genetic interactions of SNAREs syntaxin/unc-64 and SNAP-25/ric-4 with daf-2, daf-7, nhr-49, sbp-1 and mdt-15 in regulating fat storage were further investigated. The tissue-specific activities of unc-64 and ric-4 were investigated to study the roles of unc-64 and ric-4 in regulating fat storage in the nervous system and/or the intestine. Results Mutations of genes required for the formation of presynaptic neurotransmission site did not obviously influence fat storage. However, among the genes required for synaptic function, the plasma membrane-associated SNAREs syntaxin/unc-64 and SNAP-25/ric-4 genes were involved in the fat storage control. Fat storage in the intestinal cells was dramatically increased in unc-64 and ric-4 mutants as revealed by Sudan Black and Nile Red strainings, although the fat droplet size was not significantly changed. Moreover, in both the nervous system and the intestine, expression of unc-64 significantly inhibited the increase in fat storage observed in unc-64 mutant. And expression of ric-4 in the nervous system completely restored fat storage in ric-4 mutant. Genetic interaction assay further indicated that both unc-64 and ric-4 regulated fat storage independently of daf-2 [encoding an insulin-like growth factor-I （IGF-I） receptor], daf-7 [encoding a transforming growth factor-β （TGF-β） ligand], and nhr-49 （encoding a nuclear hormone receptor）. Besides, mutation of daf-16 did not obviously affect the phenotype of increased fat storage in unc-64 or ric-4 mutant. Furthermore, unc-64 and ric-4 regulated fat storage probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways. In addition, fat storage in unc-64; ric-4 was higher than that in either unc-64 or ric-4 single mutant nematodes, suggesting that unc-64 functions in parallel with ric-4 in regulating fat storage. Conclusion The plasma membrane-associated SNAREs syntaxin/ unc-64 and SNAP-25/ric-4 function in parallel in regulating fat storage in C. elegans, probably through the ARC105/mdt-15- and SREBP/sbp-1-mediated signaling pathways.

HLB-1 functions as a new regulator for the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans

Objective To study the role of HLB-1 in regulating the organization and function of neuromuscular junctions in nematode Caenorhabditis elegans. Methods To evaluate the functions of HLB-1 in regulating the organization and function of neuromuscular junctions, effects of hlb-1 mutation on the synaptic structures were revealed by uncovering the expression patterns of SNB-1 ：：GFP and UNC-49：GFP, and pharmacologic assays with aldicarb and levamisole were also used to test the synaptic functions. Further rescue and mosaic analysis confirmed HLB-1＇s role in regulating the organization and function of neuromuscular junctions. Results Loss of HLB-1 function did not result in defects in neuronal outgrowth or neuronal loss, but caused obvious defects of SNB-1：：GFP and UNC-49：：GFP puncta localization, suggesting the altered presynaptic and postsynaptic structures. The mutant animals exhibited severe defects in locomotion behaviors and altered responses to an inhibitor of acetylcholinesterase and a cholinergic agonist, indicating the altered presynaptic and postsynaptic functions. Rescue and mosaic analysis experiments suggested that HLB-1 regulated synaptic functions in a cell nonautonomously way. Moreover, HLB- 1 expression was not required for the presynaptic active zone morphology. Genetic evidence further demonstrated that hlb-1 acted in a parallel pathway with syd-2 to regulate the synaptic functions. Conclusion HLB-1 appeared as a new regulator for the organization and function of neuromuscular junctions in C. elegans.

Artificial nociceptor based on TiO nanosheet memristor

With the development of technology,the learning and memory functions of artificial memristor synapses are necessary for realizing artificial neural networks and neural neuromorphic computing.Owing to their high scalability performance,nanosheet materials have been widely employed in cellular-level learning,but the behaviors of nociceptor based on nanosheet materials have rarely been studied.Here,we present a memristor with an Al/TiO_(2)/Pt structure.After electroforming,the memristor device showed a gradual conductance regulation and could simulate synaptic functions such as the potentiation and depression of synaptic weights.We also designed a new scheme that verifies the pain sensitization,desensitization,allodynia,and hyperalgesia behaviors of real nociceptors in the fabricated memristor.Memristors with these behaviors can significantly improve the quality of intelligent electronic devices.Data fitting showed that the high resistance and low resistance states were consistent with the hopping conduction mechanism.This work promises the application of TiO_(2)-based devices in next-generation neuromorphological systems.

Dysfunction of Wnt signaling and synaptic ：lisassembly in neurodegenerative diseases

The molecular mechanisms that regulate synapse formation have been well documented. However, little is known about the factors that modulate synaptic stability. Synapse loss is an early and invariant feature of neurodegenerative diseases including Alzheimer＇s lAD） and Parkinson＇s disease. Notably, in AD the extent of synapse loss correlates with the severity of the disease. Hence, understanding the molecular mechanisms that underlie synaptic maintenance is crucial to reveal potential targets that will allow the development of ther- apies to protect synapses. Writs play a central role in the formation and function of neuronal circuits. Moreover, Wnt signaling compo- nents are expressed in the adult brain suggesting their role in synaptic maintenance in the adult. Indeed, blockade of Wnts with the Wnt antagonist Dickkopf-1 （Dkkl） causes synapse disassembly in mature hippocampal cells. Dkkl is elevated in brain biopsies from AD patients and animal models. Consistent with these findings, Amyloid-β （Aβ） oUgomers induce the rapid expression of Dkkl. Importantly, Dkkl neutralizing antibodies protect synapses against Aβ toxicity, indicating that Dkkl is required for Aβ-mediated synapse loss. In this review, we discuss the role of Wnt signaling in synapse maintenance in the adult brain, particularly in relation to synaptic loss in neurodegenerative diseases.