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

Abstract

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 Ca 2+ permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca 2+ 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.

Exposure to an Environmental Neurotoxicant Hastens the Onset of Amyotrophic Lateral Sclerosis-Like Phenotype in Human Cu2+/Zn2+ Superoxide Dismutase 1 G93A Mice: Glutamate-Mediated Excitotoxicity

“…This could, in theory, lead to a greater proportion of Ca 2ϩ -permeable AMPA receptors, which could increase glutamate-induced motor neuron excitotoxicity caused by increased [Ca 2ϩ ] i . In addition, Yin et al (2007) demonstrated that intrathecal infusion of NAS reduced motor neuron loss in G93A rats. This effect presumably is caused by action on Ca 2ϩ -permeable AMPA receptors.…”

The proteasomal system

“…The answer may be found in the functionality of these specialized neurons: if the AMPA glutamate receptors are blocked, the viability of the cells increases and the amount of mutant SOD1 inclusions formed is reduced (Yin et al, 2007;Tortarolo et al, 2006;Tateno et al, 2004;Rembach et al, 2004).…”

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

“…However, a marked loss of ventral-horn EAAT2 was observed, along with substantial motor-neuron damage, before onset of symptoms (90-100 days) in the SOD1-G93A rats. Compared with sham-treated SOD1-G93A animals, 30-day NAS infusions (starting at approximately 70 days of age) markedly diminished the loss of both motor neurons and of astrocytic EAAT2 labeling (157). Interestingly, a recent study showed that, under normal conditions, astrocytes regulate the expression and subunit composition of the AMPA receptors in motor neurons.…”

“…In support of a crucial role for GluR2 in controlling Ca 2þ influx through the AMPA-receptor complex, the evidence indicates that the overexpression of a GluR2-deficient Ca 2þ -permeable AMPA receptor in mice leads to a late-onset motorneuron degenerative disorder, which is exacerbated when coexpressed with the mutant SOD1 transgene (78,79). To assess the role of Ca 2þ -permeable AMPA receptors on the evolution of ALS pathology in vivo, Yin and colleagues (157) examined the effects of prolonged intrathecal infusion of the AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in SOD1-G93A transgenic rat. In wild-type animals, immunoreactivity for EAAT2 was particularly strong around ventral horn motor neurons.…”