title: NMDA receptor activation regulates sociability by its effect on mTOR signaling activity.
abstract: Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Burket
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Benson
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Tang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States. Electronic address: deutscsi@evms.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Deutsch
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D058570:TOR Serine-Threonine Kinases
keywords: D-Cycloserine; NMDA receptor; Sociability; Tuberous sclerosis; mTOR