Intrathecal infusion of a Ca2+ permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter GLT-1 in a mutant SOD1 rat model of ALS

摘要

Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca²⁺ permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca²⁺ overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 d) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham treated G93A animals, 30 day NAS infusions (starting at 67±2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes.