Retrograde Changes in Presynaptic Function Driven by Dendritic mTORC1

Neuroscience Graduate Program, Molecular and Behavioral Neuroscience Institute, Life Sciences Institute, and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2012; 32(48):17128-42. DOI: 10.1523/JNEUROSCI.2149-12.2012
Source: PubMed


Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC1), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORC1 as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORC1 activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic terminals. This novel mode of synaptic regulation conferred by dendritic mTORC1 is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatic trans-synaptic control of presynaptic function. Our findings thus reveal that mTORC1-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORC1 signaling.

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    • "BDNF signaling and mTOR activation enhance synaptogenesis and promote synapse unsilencing in cortex (Itami et al., 2003; Luikart and Parada, 2006; Hoeffer and Klann, 2010; Shen and Cowan, 2010). In addition, BDNF can enhance pre-synaptic function (Henry et al., 2012). Our biochemical data show mTOR is localized close to synapses, as evident by its presence in our synaptoneurosome preparations. "
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    ABSTRACT: A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior. DOI:
    eLife Sciences 10/2014; 3(3). DOI:10.7554/eLife.03581 · 9.32 Impact Factor
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    • "NBQX-or CNQX-mediated blockade of AMPA receptors in the absence of TTX induces two main homeostatic responses: (1) incorporation of new, GluA2-lacking AMPA receptors postsynaptically; and (2) a retrograde signaling process that results in increased presynaptic release properties, such as spontaneous miniature frequency (Thiagarajan et al., 2005; Gong et al., 2007). Similar to the Drosophila system, postsynaptic mammalian Target of Rapamycin Complex1 (mTORC1) drives this retrograde signaling process—albeit through release of Brain-Derived Neurotrophic Factor (BDNF), which is not found in Drosophila (Henry et al., 2012). Also resonant with the Drosophila NMJ, coincident application of a cocktail of N-and P/Q-type calcium channel blockers ω-conotoxin GVIA and ω-agatoxin IVA (CTx/ATx cocktail) completely abolishes the enhanced presynaptic activity induced by 3 h of CNQX exposure (Jakawich et al., 2010). "
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    ABSTRACT: Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response-homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies-such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.
    Frontiers in Cellular Neuroscience 02/2014; 8:40. DOI:10.3389/fncel.2014.00040 · 4.29 Impact Factor
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    • "Interestingly, increased synthesis of synaptic proteins is observed in several animal models of autism [5], [6], [75] and exome sequencing of autistic patients has identified several de novo mutations in genes involved in regulation of protein synthesis [76], [77]. In neurons mTOR is known to be involved in regulation of protein synthesis and synaptic transmission [36], [78]–[82] and dysregulation of mTOR activity has been implicated in ASD [35], [83], [84]. In fact genetic removal of P70S6 kinase, the primary substrate of mTOR, or suppression of mTOR-mediated translation, can rescue phenotypic alterations in mouse models of ASD [5], [34], [38]. "
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    ABSTRACT: Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability (ID) and autism spectrum disorders (ASD). Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). De novo genetic mutations of the synaptic GTPase-activating protein (SynGAP) are associated with ID and ASD. SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength. However, exactly how SynGAP acts to maintain synaptic AMPAR content is unclear. We show here that SynGAP limits excitatory synaptic strength, in part, by suppressing protein synthesis in cortical neurons. The data presented here from in vitro, rat and mouse cortical networks, demonstrate that regulation of translation by SynGAP involves ERK, mTOR, and the small GTP-binding protein Rheb. Furthermore, these data show that GluN2B-containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation-dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks.
    PLoS ONE 12/2013; 8(12):e83941. DOI:10.1371/journal.pone.0083941 · 3.23 Impact Factor
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