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.

Keywords: D-Cycloserine; NMDA receptor; Sociability; Tuberous sclerosis; mTOR.

Fig. 1

The figure is a cartoon depiction of hypothesized mechanisms by which NMDA receptor activation dampens mTOR signaling and, thereby, improves socialization in several syndromic (e.g., Tuberous Sclerosis Complex) and nonsyndromic forms of autism spectrum disorders. Panel A depicts heightened mTOR signaling activity in several syndromic and nonsyndromic forms of autism spectrum disorders, whereas Panel B depicts two possible consequences of NMDA receptor activation. NMDA receptor activation (Panel B) decreases the activity of specific cationic amino acid transporters (CAT 1/3) responsible for arginine uptake into the neuron. Arginine is detected by nutrient sensors, which contribute to regulation of mTOR signaling activity; lowered intraneuronal concentrations of arginine lead to dampening of mTOR signaling activity. NMDA receptor activation (Panel B) also leads to the Ca²⁺-dependent activation of calcineurin, a phosphatase that activates STEP, which, in turn, dephosphorylates and inactivates ERK1/2. Phosphorylated ERK1/2 is a major driver of mTOR signaling activity. NMDA receptor activation may be preferred to direct inhibition of mTORC1 in disorders requiring chronic, even lifelong, treatment, such as autism spectrum disorders (see text for additional derails).