The Therapeutic Effect of Memantine Through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome

Background:  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. 

Objectives:  The aim of this study is to determine the possible mechanism through which memantine exerts its therapeutic effects on autism. 

Methods:  C57BL/6 fragile X mice was derived from C57BL/6-129 hybrid mice carrying the Fmr1 knockout mutation. Cerebellar granule cells (CGCs) were prepared from wild type (WT) and Fmr1 knockout (KO) 5-6 day postnatal pups. When required, the CGCs were treated for 72 h with memantine (Sun Pharma) at a concentration of 100 μM. Cell adhesion assay and cell migration assay were carried out to examine the adhesion and migration properties of CGCs. The expression of synaptic vesicle proteins was tested using the fluorescence staining. The DiI labeling was used to outline dendritic spines in pyramidal neurons.  

Results:  In this study, we used cultured cerebellar granule neural 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 rescued dendritic spine defects in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the reduced excitatory synapses in Fmr1-KO CGCs.

Conclusions:  These findings suggest that memantine may exert its therapeutic capacity though a stimulatory effect on dendritic spines maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.