Blockade of Serotonin 5-HT6 Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT6 receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT6 receptors contribute to increased mTOR activity in the brain of Nf1+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT6 receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT6 receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT6 receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients.

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

“…An important feature of the 5-HT 6 R is its high level of ligand-independent constitutive activity, which corresponds to the ability of a receptor to be active even in the absence of an agonist [10]. The role of 5-HT 6 R constitutive activity at canonical Gs signaling and non-canonical signaling has been described in various pathophysiological conditions [11][12][13][14][15]. Consistent with those findings, the development of 5-HT 6 R ligands acting as inverse agonists and/or neutral antagonists at the different 5-HT 6 R-operated signaling pathways is of utmost interest to decipher the cellular mechanism(s) under the control of the various 5-HT 6 R signal transduction mechanisms and of constitutive vs. agonist-dependent receptor activation.…”

Pathophysiology of the Serotonin System in the Nervous System and Beyond

“…Numerous 5-HT receptors participate in cognitive processes and alteration of their activities might sustain cognitive deficits. Doucet et al reported strong evidence for the aberrant constitutive activity of 5-HT 6 receptors in a mouse model of neurofibromatosis type 1 (NF1), the nf1+/− mice [6]. This model resumes some of the cognitive deficits of the human disease.…”