Treatment of the Ppt1–/– Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis With the N-methyl-d-aspartate (NMDA) Receptor Antagonist Memantine

Abstract

The neuronal ceroid lipofuscinoses, a family of neurodegenerative lysosomal storage disorders, represent the most common cause of pediatric-onset neurodegeneration. The infantile form has a devastatingly early onset and one of the fastest-progressing disease courses. Despite decades of research, the molecular mechanisms driving neuronal loss in infantile neuronal ceroid lipofuscinosis remain unknown. We have previously shown that N-methyl-d-aspartate (NMDA)–type glutamate receptors in the Ppt1–/– mouse model of this disease exhibit a hyperfunctional phenotype and postulate that aberrant glutamatergic activity may contribute to neural pathology in both the mouse model and human patients. To test this hypothesis, we treated Ppt1–/– mice with the NMDA receptor antagonist memantine and assessed their response to the drug using an accelerating rotarod. At 20 mg/kg, memantine treatment induced a delayed but notable improvement in Ppt1–/– mice. Much remains to be assessed before moving to patient trials, but these results suggest memantine has potential as a treatment.