Abstract
Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR's role in synaptic transmission may be complex-specific. To better understand their roles in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs (eEPSCs), however, the effects of mTORC1 on eEPSCs were postsynaptic and the effects of mTORC2 were presynaptic. Despite postsynaptic inhibition of evoked release, mTORC1 inactivation enhanced spontaneous vesicle fusion and replenishment, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.
Highlights
The mechanistic target of rapamycin signaling network is an evolutionarily conserved group of interacting proteins centered around the ubiquitously expressed serine/threonine kinase mTOR
To investigate the effects of mTORC1 or mTORC2 inactivation on neurons, we cultured primary hippocampal neurons isolated from P0-P1 Raptorflox/flox or Rictorflox/flox mice on astrocytes isolated from P0-P1 wild-type mice
At the time of plating, we transduced the neurons with adeno-associated viruses (AAVs) expressing either an mCherry-Cre fusion protein or mCherry alone, both driven by the SYN promoter, to generate knockout (Raptor-KO or Rictor-KO) or control (Raptor-Con neurons (Con) or RictorCon) neurons, respectively
Summary
The mechanistic target of rapamycin (mTOR) signaling network is an evolutionarily conserved group of interacting proteins centered around the ubiquitously expressed serine/threonine kinase mTOR. Several recent studies have uncovered roles for IGF-1 receptor signaling, protein synthesis, and cholesterol biosynthesis in regulating the balance of spontaneous and evoked SV release (Gazit et al, 2016; Scarnati et al, 2018; Wasser et al, 2007) Because these processes are up- and downstream of mTOR, this raises the possibility that mTOR may act as a hub to regulate different modes of SV fusion. Our results showed that both mTOR complexes were necessary to support normal neuron growth and evoked excitatory synaptic transmission Despite these similarities, the effects of mTORC1 on evoked EPSCs (eEPSCs) were postsynaptic, via reductions in synapse number, whereas mTORC2 regulated the presynaptic Ca2+ dependence of evoked SV release. Via differential activation of these two complexes, the mTOR pathway is ideally poised to respond to external cues and make fine adjustments to glutamatergic synaptic transmission to maintain normal neural network function
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