Activity dependent changes in synaptic structure and function are often dependent on the spatially regulated translation of dendritically localized mRNAs. Despite growing interest in local protein synthesis in neurons, there is a fundamental gap in our understanding of how changes in activity differentially regulate the translation of specific mRNAs and how this process is altered in neuropathologies related to cognitive impairment and mental retardation. Recent work has established a pivotal role for the mammalian target of rapamycin complex 1 (mTORC1) in regulating the translation of subsets of mRNAs in the dendrite in response to stereotyped pat- terns of stimulation. mTORC1 is essential for certain forms of long-lasting synaptic plasticity, such as the induction of late phase-LTP in the hippocampus. However, a unique role for mTORC1 in homeostatic forms of synaptic plasticity, in which compensatory changes in synapse strength are implemented as a form of negative feedback, is less clear. The long-term goal of this research is to understand the contribution of dendritic pro- tein synthesis to the induction and maintenance of homeostatic changes in synaptic strength. The objective of this particular application is to elucidate the role played by mTORC1 signaling in a novel form of homeostatic plasticity involving fast acting, postsynaptic modulation of presynaptic function via dendritic secretion of brain-derived neurotrophic factor (BDNF) as a retrograde signal. The central hypothesis is that postsynaptic mTORC1 signaling regulates a local translational program in dendrites that functions to modulate neurotransmitter release from apposed presynaptic terminals. Guided by extensive preliminary data collected in the applicant's laboratory, this hypothesis will be address by pursuing the following two aims: 1) Determine if postsynaptic mTORC1 signaling is necessary and sufficient for homeostatic regulation of presynaptic function;and 2) determine the extent to which mTORC1 operates locally in dendrites to regulate BDNF translation and enhance presynaptic function after AMPAR blockade.
Under Aim 1, changes in presynaptic efficacy will be assessed via electrophysiology and immunofluorescence under conditions of cell specific activation or inhibition of mTORC1. These manipulations depend on a previously established genetic approach which has been proven feasible in the applicant's hands.
Under Aim 2, experiments will involve spatially restricted manipulation of mTORC1 activity in combination with immunofluorescence analyses to examine changes in BDNF expression and presynaptic function in small dendritic regions. The experiments outlined in this proposal are expected to reveal novel links between postsynaptic regulation of mTORC1 function, local dendritic BDNF synthesis, and retrograde modulation of presynaptic function. By characterizing a unique role for local protein synthesis under control of mTORC1, this project is genuinely innovative and has the potential to provide a foundation on which to establish novel targets of therapeutic intervention for neurological disorders such as tuberous sclerosis complex and ASD, as well as significantly advance the field of synaptic plasticity at large.
Several diseases that result in cognitive impairment and mental retardation have been associated with dysregulation of local protein synthesis in dendrites, specifically via overactive signaling of mTOR complex 1 (mTORC1). While several diseases related to Autism spectrum disorders, such as fragile X syndrome, tuberous sclerosis complex, and PTEN harmatoma syndrome, are all associated with overactive mTORC1 signaling in the nervous system, it is not clear how this signaling alters the function of synaptic connections between neurons to cause the behavioral and cognitive abnormalities seen in these disorders. This project will explore the role of mTORC1 in controlling synapse function in the hippocampus, a brain structure known to play a pivotal role in learning and memory, and will thus provide insights for targeting this signaling pathway as a therapeutic option for autism spectrum disorders.
|Henry, Fredrick E; McCartney, Amber J; Neely, Ryan et al. (2012) Retrograde changes in presynaptic function driven by dendritic mTORC1. J Neurosci 32:17128-42|
|Henry, Fredrick E (2011) A Fragile Balance at Synapses: New Evidence Supporting a Role for FMRP in Homeostatic Plasticity. J Neurosci 31:6617-9|