Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism

Abstract

SUMMARY While beneficial effects of fasting on organismal function and health are well appreciated, we know little about the molecular details of how fasting influences synaptic function and plasticity. Our genetic and electrophysiological experiments demonstrate that acute fasting blocks retrograde synaptic enhancement that is normally triggered as a result of reduction in postsynaptic receptor function at the Drosophila larval neuromuscular junction (NMJ). This negative regulation critically depends on transcriptional enhancement of eukaryotic initiation factor 4E binding protein (4E-BP) under the control of the transcription factor Forkhead box O (Foxo). Furthermore, our findings indicate that postsynaptic 4E-BP exerts a constitutive negative input, which is counteracted by a positive regulatory input from the Target of Rapamycin (TOR). This combinatorial retrograde signaling plays a key role in regulating synaptic strength. Our results provide a mechanistic insight into how cellular stress and nutritional scarcity could acutely influence synaptic homeostasis and functional stability in neural circuits.

Skeletal muscle mTORC1 regulates neuromuscular junction stability

“…In drosophila, it has been shown that reduction in TOR signalling in muscle fibres is sufficient to compromise synaptic plasticity through retrograde signalling . Interestingly, this TOR/4E‐BP1‐dependent mechanism acts also during short time periods, like starvation . The idea that retrograde signalling affects the stability of the motor neuron is in line with the fact that we observe significant alterations of the motor neuron by electron microscope.…”

“…39 Interestingly, this TOR/4E-BP1-dependent mechanism acts also during short time periods, like starvation. 40 The idea that retrograde signalling affects the stability of the motor neuron is in line with the fact that we observe significant alterations of the motor neuron by electron microscope. Multiple factors have been proposed to be secreted by muscle fibres and are important in NMJ maintenance, particularly during stress conditions.…”

Disparate Postsynaptic Induction Mechanisms Ultimately Converge to Drive the Retrograde Enhancement of Presynaptic Efficacy

“…Although these perturbations each disrupt receptors and lead to adaptive increases in presynaptic neurotransmitter release, PhTx- and GluRIIA -mediated PHP signaling exhibit important differences. First, some genes have been identified that are only necessary for GluRIIA -dependent PHP expression, while PHP is robustly expressed following acute PhTx application in larvae with mutations in these genes (Frank et al, 2009; Kauwe et al, 2016; Penney et al, 2016; Spring et al, 2016; Tsurudome et al, 2010). In addition, PhTx-induced PHP expression is translation-independent (Frank et al, 2006), while GluRIIA -induced PHP is blocked by inhibitions to postsynaptic translation through loss of the translational regulator Target of Rapamycin ( Tor ) (Kauwe et al, 2016; Penney et al, 2012).…”

“…First, some genes have been identified that are only necessary for GluRIIA -dependent PHP expression, while PHP is robustly expressed following acute PhTx application in larvae with mutations in these genes (Frank et al, 2009; Kauwe et al, 2016; Penney et al, 2016; Spring et al, 2016; Tsurudome et al, 2010). In addition, PhTx-induced PHP expression is translation-independent (Frank et al, 2006), while GluRIIA -induced PHP is blocked by inhibitions to postsynaptic translation through loss of the translational regulator Target of Rapamycin ( Tor ) (Kauwe et al, 2016; Penney et al, 2012). Although several genes and mechanisms necessary for the expression of PHP in the presynaptic neuron have been identified (Dickman and Davis, 2009; Frank, 2013; Kiragasi et al, 2017), far less is known about the mechanistic differences in postsynaptic transduction between PhTx- and GluRIIA -induced PHP signaling.…”

Sarcopenia: Tilting the Balance of Protein Homeostasis

“…Denervation‐evoked impairment of muscle function will result in further muscle disuse, which may exacerbate muscle atrophy with age . In support of the abovementioned notion, studies involving Drosophila showed that TOR and 4E‐BP activity in the muscle tissue retrogradely enhanced presynaptic neurotransmitter release at the neuromuscular junction, while in a mouse model, 4EBP‐regulated cap translation promoted synaptic refinement between neurons in the absence of postsynaptic activity . Taken together, these studies showed that the mTOR/AKT pathway plays a role in regulating the neuronal connectivity with muscle fibers, likely through influencing protein synthesis and degradation in the muscle.…”