Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission.
The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism, and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by ∼50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed, and the miniature event size. Prolonged (72 h) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications, depending on where in the brain mutations of an mTOR suppressor gene occur.
The Cain Foundation Laboratories, The Jan and Dan Duncan Neurological Research Institute, Houston, Texas 77030, USA.
Matthew C
MC
Weston
Hongmei
H
Chen
John W
JW
Swann
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D003342:Corpus Striatum / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism* / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology; D000070584:Tripartite Motif Proteins
D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D005971:Glutamates; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D020123:Sirolimus; D026941:Sodium Channel Blockers; D058570:TOR Serine-Threonine Kinases; D013779:Tetrodotoxin; D044767:Ubiquitin-Protein Ligases; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D005680:gamma-Aminobutyric Acid; C493465:Slc17a7 protein, mouse; C492244:Viaat protein, mouse; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins; C546843:mTOR protein, mouse; C487757:Pten protein, mouse