Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction

Disorders of neuronal migration in cerebral cortex are associated with neur ological impairments, including mental retardation and epilepsy. Their caus es and pathophysiology remain largely unknown, however. in patients with Ze llweger disease, a lethal panperoxisomal disorder, and in mice lacking the Pxr1 import receptor for peroxisomal matrix proteins, the absence of peroxi somes leads to abnormal neuronal migration. Analysis of Pxr1(-/-) mice reve aled that the migration defect was caused by altered N-methyl-D-aspartate ( NMDA) glutamate receptor-mediated calcium mobilization. This NMDA receptor dysfunction was linked to a deficit in platelet-activating factor, a phenom enon related to peroxisome impairment. These findings confirm NMDA receptor involvement in neuronal migration and suggest a link between peroxisome me tabolism and NMDA receptor efficacy.