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 mTORCl in neurons (e.g., cerebellar Purkinje cells). mTORCl 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 mTORCl, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORCl overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORCl 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 mTORCl 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.

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

“…Surprisingly, we find that cortical excitatory neurons in fact show an opposite downregulation trend for both types of processes, indicating that they respond to the loss of FMRP differently than inhibitory neurons and possibly are reflecting a decrease in mTOR activity. Indeed, stimulation of the N-methyl-D-aspartate receptor (NMDAR) decreases mTOR signaling activity [96][97][98] . We find that NMDAR subunits are most highly expressed in excitatory neurons ( Figure S4a).…”

New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs

“…The sustained activation of the N‐methyl‐D‐aspartate receptor (NMDA) receptor provides inhibitory action on the mTORC1 signalling activity, resulting in reduced protein synthesis . NMDA activation is associated with dephosphorylation of extracellular signal‐related kinase (ERK) protein kinase B (PKB/Akt) and activation of glycogen synthase kinase‐3 (GSK‐3) . PKB/Akt proteins and ERK inhibit tuberous sclerosis (TSC1 and TSC2) complexes, which are inhibitors of mTOR .…”

“…NMDA activation is associated with dephosphorylation of extracellular signal‐related kinase (ERK) protein kinase B (PKB/Akt) and activation of glycogen synthase kinase‐3 (GSK‐3) . PKB/Akt proteins and ERK inhibit tuberous sclerosis (TSC1 and TSC2) complexes, which are inhibitors of mTOR . Therefore, PKB/Akt and ERK activate the mTOR signalling pathway, while GSK3 activity leads to increased TSC1/2 activity, thus inhibiting the mTOR pathway .…”

“…The action of ketamine occurred on ERK, PKB/Akt and signalling pathways of growth factors linked to the activation of mTOR. The antidepressant effect exerted by ketamine requires the inhibition of GSK‐3 , which inhibits mTOR signalling . Importantly, inhibition of GSK‐3 by lithium or agents that preferentially inhibit the GSK‐3β potentiated and increased the duration of antidepressants and synaptogenic effects of the ketamine, through activation of the mTORC1 .…”

The α7 nicotinic acetylcholine receptor: A mediator of pathogenesis and therapeutic target in autism spectrum disorders and Down syndrome

“…In vitro evidence from primary cortical neuron cultures of E17-19 Į7-KO and wild-type mice was also consistent with an effect of ablated Į 7 nAChR expression on maturation of GABAergic neurons. The Į7-KO mice were also shown to have diminished expression of NMDA receptors and diminished levels of D-serine, an endogenous glycinergic co-agonist; importantly, NMDA receptor hypofunction is independently associated with ASD [27,[29][30][31][32][33]. Thus, given the important relationships between normal function of Į 7 nAChR-and NMDA receptor-mediated neurotransmission and the synchronized oscillatory output of pyramidal cell neurons, it is not surprising that defective transduction of the acetylcholine signal is implicated in the pathogenesis of ASD [2,10,23,27,28].…”