New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.
Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives.
Departament de Ciències Experimentals i de la Salut. Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Arnau
A
Busquets-Garcia
Departament de Ciències Experimentals i de la Salut. Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Rafael
R
Maldonado
Departament de Ciències Experimentals i de la Salut. Universitat Pompeu Fabra, 08003 Barcelona, Spain. Electronic address: andres.ozaita@upf.edu.
Andrés
A
Ozaita
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics; D018079:Receptors, GABA / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D018079:Receptors, GABA; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
Anxiety; Autism; CB1 cannabinoid receptor; Endocannabinoid system; Epilepsy; Fragile X syndrome; Intellectual disability; Mammalian target of rapamycin (mTOR); Nociception; mGluR5