Structural Synaptic Plasticity Under Different Neural Network Avtivity Levels And Mechanism Underlying G59s In P150^glued Related Neurodegeneration

Neural activity modulates synaptic efficacy, as well as the development and maintenance of synaptic connections. Activity can also regulate the content of cytoskeleton protein Actin which is highly enriched at dendritic spines that mediate most of the excitatory synaptic transmission in the brain. During the development of neural networks, the degree of Actin polymerization in the spines is gradually enhanced with the increase of postsynaptic terminals efficacy. However, the role of neural network activity in the structural development of synapses remains unclear. In order to address this question, we used TTX to chronically block spike activities globally in both developing and more mature cultured hippocampal neurons from embryonic rats. We found that the content of Actin in spines as well as the spine density was significantly increased by globally chronic TTX treatment in developing but not in relative mature neurons, suggesting that activity is crucial during developmental regulation of long-term synaptic structural plasticity. Our results indicate that in different developmental phases, Actin content in spines and postsynaptic efficacy are unlikely regulated by the activity level of neuronal network, which providing a new angle of view to understand synaptic plasticity as well as a novel clue to study the machnisms underlying homeostasis plasticity.The microtubule motor cytoplasmic dynein and its activator dynactin work together as a complex to drive vesicular transport and mitotic spindle organization. Dynactin is ubiquitously expressed in eukaryotes, but a G59S mutation in the P150^Glued subunit of dynactin leads to the specific degeneration of motor neurons. We found this mutation in the conserved cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain lowers the affinity of P150^Glued for F-box protein FBXL5 with its turnover via ubiquitination is disrupted by the improper folding of the CAP-Gly domain, resulting in aggregation of the P150^Glued protein both in vitro and in vivo.