title: The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.
abstract: Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.
authors.affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, New York, New York, United States of America.
authors.forename: Hongen
authors.initials: H
authors.lastname: Wei
authors.forename: Carl
authors.initials: C
authors.lastname: Dobkin
authors.forename: Ashfaq M
authors.initials: AM
authors.lastname: Sheikh
authors.forename: Mazhar
authors.initials: M
authors.lastname: Malik
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D008559:Memantine; C497684:Fmr1 protein, mouse