Novel Roles for mTORC1-dependent Translational Control during Synaptic Homeostasis.

Neuroscience;Plasticity;Synapse;MTOR;Autism;Physiology;Science;Neuroscience

Henry, Fredrick E.Stuenkel, Edward L. ;

University of Michigan

关键词: Neuroscience;    Plasticity;    Synapse;    MTOR;    Autism;    Physiology;    Science;    Neuroscience;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/107207/fehenry_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The mechanistic target of rapamycin complex 1 (mTORC1), a kinase involved in regulating translation initiation, has recently emerged as a critical player responsible for orchestrating dynamic changes in local protein synthesis in response to altered synaptic activity. Here we identify a novel mode of synaptic regulation conferred by mTORC1-dependent signaling in dendrites, wherein mTORC1 activation gates a local retrograde signaling mechanism that drives changes in presynaptic function from apposed postsynaptic terminals. This unique role for dendritic mTORC1 signaling is critically dependent on BDNF release, which couples loss of excitatory synaptic drive with retrograde compensation of presynaptic function. Acute activation of mTORC1 signaling using the lipid second messenger phosphatidic acid (PA) or overexpression of the endogenous mTOR activator RhebGTPase exerts a powerful influence on network function, which is also dependent on dendritic synthesis of BDNF as a retrograde signal. We identify an additional feature of the putative postsynaptic homeostatic sensor mechanism, showing that phospholipase D (PLD)-mediated hydrolysis of the lipid second messenger phosphatidic acid (PA) is a crucial component of the signaling pathway which relays homeostatic signals to postsynaptic mTORC1 after loss of excitatory input. Lastly, we find that mTORC1-dependent retrograde signaling acts in coordination with dynamic relocalization of the ubiquitin proteasome system to and from axonal boutons to regulate presynaptic function in the expression of synaptic homeostasis. Increasing neuronal firing rates enriches proteasome accumulation at synaptic terminals, whereas inhibiting neuronal firing results in a dramatic redistribution away from synaptic terminals. This altered localization is due, at least in part, to an activity-dependent sequestration mechanism at presynaptic terminals. Moreover, activity-dependent phosphorylation of the Rpt6 subunit of the 19S proteasome is necessary and sufficient for axonal proteasome redistribution, and this altered localization plays a critical role in establishing mTORC1-dependent retrograde homeostatic changes in presynaptic function after loss of postsynaptic drive. Several monogenic neurodevelopmental conditions related to Autism Spectrum Disorder and Intellectual Disability share the common molecular phenotype of increased mTORC1 signaling. As such, a more thorough understanding of how mTORC1 regulates synaptic function may provide insights for targeting this signaling pathway as a therapeutic option for cognitive dysfunction.