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.
Highlights
Neurofibromatosis type 1 (NF1) is a dominant autosomal disease with an estimated prevalence of about 1 in 3000 that is independent of ethnicity, race, or gender, and with a full penetrance
Reduced 5-HT6 receptor-operated mechanistic Target of Rapamycin (mTOR) signaling has been involved in memory enhancement elicited by dietary restriction in the mouse [24]. These findings suggest that blocking the 5-HT6 receptor-mTOR pathway might be a promising strategy to alleviate cognitive deficits associated with neuropsychiatric disorders of different etiologies [20,22,25,26,27]. In light of these observations and the previously established physical and functional interactions between the 5-HT6 receptor and neurofibromin, we investigated the impact of inhibiting 5-HT6 receptor or mTOR activation on social cognition and associative memory in mice with a heterozygous null mutation in the NF1 gene (Nf1+/− mice), a well-characterized preclinical model of NF1 that recapitulates some behavioral features of the disease [28,29,30,31,32]
We show that the acute injection of SB258585, a 5-HT6 receptor antagonist that behaves as inverse agonist [23], or of rapamycin, a mTOR inhibitor, abolishes deficits in long-term social and associative memories in Nf1+/− mice and reduces mTOR overactivation in the prefrontal cortex (PFC) of these mice
Summary
Neurofibromatosis type 1 (NF1) is a dominant autosomal disease with an estimated prevalence of about 1 in 3000 that is independent of ethnicity, race, or gender, and with a full penetrance. The hallmarks of the disease are “café au lait” spots and tumors of central and peripheral nervous systems, including neurofibromas, gliomas and pheochromocytomas [1]. Cognitive deficits represent another major feature of the disease, with up to 80%. Of the children with NF1 at risk of moderate to severe cognitive impairments that affect one or more areas of cognitive functioning and seriously compromise their scholar performance and quality of life [2,3] These include learning disability, decreased attention, difficulties in executive planning and deficits in perception skills [4,5,6]. Clinical trials assessing the effect of statins or methylphenidate upon behavioral and cognitive outcomes yielded mitigated or poorly reproducible results [11,12,13,14,15], underscoring the need of new therapeutic strategies
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