5‐HT ₆ receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia

Abstract

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.

Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity

“…Our previous studies of the 5-HT 6 receptor interactome identified neurofibromin as a candidate receptor partner (12). Immunoprecipitation followed by Western blot analysis confirmed the interaction of endogenously expressed neurofibromin with human (HA)-tagged 5-HT 6 receptor expressed in neuroblastoma-glioma NG108-15 cells (Fig.…”

“…In addition to its coupling to G proteins, the 5-HT 6 receptor interacts with the Src family tyrosine kinase Fyn (9), the Jun activation domain-binding protein 1 (10), and the microtubule-associated protein Map1b (11). The 5-HT 6 receptor also recruits the mammalian Target of Rapamycin (mTOR) Complex 1, and receptor-operated activation of mTOR signaling in prefrontal cortex (PFC) mediates its deleterious influence on cognition (12). Furthermore, 5-HT 6 receptors associate with and activate Cyclin-dependent kinase 5 (Cdk5) in an agonist-independent manner through mechanisms involving receptor phosphorylation by associated Cdk5 to promote migration of neurons and neurite growth (13,14).…”

“…In light of recent evidence indicating that G protein-coupled receptor (GPCR) constitutive activity can be modulated by G protein-coupled receptor-interacting proteins (GIPs) (15), we focused on neurofibromin, another 5-HT 6 receptor partner known to be involved in adenylyl cyclase activation by various GPCRs (12,16). Neurofibromin is an Ras GTPase-activating protein (Ras-GAP) encoded by the tumor suppressor gene NF1.…”

N1-Azinylsulfonyl-1H-indoles: 5-HT6 Receptor Antagonists with Procognitive and Antidepressant-Like Properties

“…1 The 5-HT 6 R belongs to the G-protein coupled receptor (GPCR) superfamily, and it stimulates adenylyl cyclase via Gs as well as extracellular-regulated kinase (ERK) signaling via the Srcfamily tyrosine kinase Fyn. Furthermore, 5-HT 6 R activates mTOR Complex 1 (mTORC1) in the prefrontal cortex, which is related to cognitive deficits, 2 and the receptor constitutively activates Cdk5 to control cortical neurons migration and promote neurite growth. 3 Blockade of 5-HT 6 R enhances cognitive performance in a broad range of tasks in rodents, 4,5 and phase II clinical studies have demonstrated efficacy of 5-HT 6 R antagonists (Iladopirdine = LuAE58054, SB742457, and AVN-211, Figure 1) in conjunction with donepezil in mild-to-moderate AD patients.…”

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

“…mTOR inhibitors were clinically approved to reduce restenosis after angioplasty for patients with vascular occlusion 63, 64. It has been reported that 5‐HT activated mTOR and p70S6K in neurons 65, 66. In the pulmonary artery, activation of p70S6K by 5‐HT induces SMC proliferation 67.…”