Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many
neurodegenerative diseases. In the case of
motor neuron disease, there is significant evidence to suggest that the overactivation of
AMPA receptors due to deficiencies in the expression and function of glial
glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial
glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial
glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST+/-/GLT1-cKO). GLAST+/-/GLT1-cKO mice (both sexes) exhibited nuclear irregularity and
calpain-mediated degradation of nuclear pore complexes (NPCs), which are responsible for nucleocytoplasmic transport. These abnormalities were associated with progressive motor neuron loss, severe
paralysis, and shortened lifespan. The nuclear export inhibitor KPT-350 slowed but did not prevent motor neuron death, whereas long-term treatment of the
AMPA receptor antagonist
perampanel and the
calpain inhibitor SNJ-1945 had more persistent beneficial effects. Thus, NPC degradation contributes to
AMPA receptor-mediated excitotoxic motor neuronal death, and preventing NPC degradation has robust protective effects. Normalization of NPC function could be a novel therapeutic strategy for
neurodegenerative disorders in which
AMPA receptor-mediated excitotoxicity is a contributory factor.SIGNIFICANCE STATEMENT Despite glial
glutamate transporter dysfunction leading to excitotoxicity has been documented in many neurological diseases, it remains unclear whether its dysfunction is a primary cause or secondary outcome of neuronal death at disease state. Here we show the combined loss of glial
glutamate transporters GLT1 and GLAST in spinal cord caused motor neuronal death and hindlimb
paralysis. Further, our novel mutant exhibits the nuclear irregularities and
calpain-mediated progressive nuclear pore complex degradation. Our study reveals that glial
glutamate transporter dysfunction is sufficient to cause motor neuronal death in vivo.