Reduction in expression of the astrocyte glutamate transporter, GLT1, worsens functional and histological outcomes following traumatic spinal cord injury

Abstract

The astrocyte glutamate transporter, GLT1, is responsible for the vast majority of glutamate uptake in the adult central nervous system (CNS), thereby regulating extracellular glutamate homeostasis and preventing excitotoxicity. Glutamate dysregulation plays a central role in outcome following traumatic spinal cord injury (SCI). To determine the role of GLT1 in secondary cell loss following SCI, mice heterozygous for the GLT1 astrocyte glutamate transporter (GLT1+/−) and wild-type mice received thoracic crush SCI. Compared to wild-type controls, GLT1+/− mice had an attenuated recovery in hindlimb motor function, increased lesion size, and decreased tissue sparing. GLT1+/− mice showed a decrease in intraspinal GLT1 protein and functional glutamate uptake compared to wild-type mice, accompanied by increased apoptosis and neuronal loss following crush injury. These results suggest that astrocyte GLT1 plays a role in limiting secondary cell death following SCI, and also show that compromise of key astrocyte functions has significant effects on outcome following traumatic CNS injury. These findings also suggest that increasing intraspinal GLT1 expression may represent a therapeutically relevant target for SCI treatment.

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

“…We have consistently observed significant GLT1 downregulation in endogenous reactive astrocyte populations in both contusion and crush, as well as both cervical and thoracic, models of SCI (Lepore et al, 2011a; Lepore et al, 2011c; Li et al, 2014b; Putatunda et al, 2014; Watson et al, 2014). When we selectively increased GLT1 expression in these endogenous astrocytes in the unilateral cervical contusion model using an AAV8 vector, we paradoxically found that secondary degeneration of PhMNs and diaphragm denervation were worsened (Li et al, 2014b).…”

“…Transplantation also provides for long-term astrocyte integration and therapeutic replacement. For example, the lasting nature of dysregulation of extracellular glutamate homeostasis after SCI (Lepore et al, 2011a; Lepore et al, 2011c) calls for longer-term maintenance of therapeutic effects, both with respect to early cell loss occurring during secondary degeneration and outcomes of SCI associated with more persistent pathophysiology of glutamate signaling such as chronic neuropathic pain (Gwak et al, 2012; Hulsebosch, 2008). …”

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

“…Failure of long-term extrasynaptic glutamate clearance is suspected to be one major cause of secondary cell loss following SCI. Noteworthy, we and others demonstrated that astrocyte GLT1 was chronically lost at the injury epicenter following SCI but also downregulated in spinal cord regions distant from the lesion core [103][104][105][106] . Furthermore, experimental data showed that the newlygenerated astrocytes arising during the SCI repair phase lacked GLT1 expression, possibly compromising long-term astrocyte glutamate homeostasis [107] .…”

FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway

“…Many studies have reported that changes in the distribution and the expression levels of GLAST and GLT-1 lead to excessive glutamate uptake, which is involved in brain injury and other neurological disorders (Coulter and Eid, 2012;Lepore et al, 2011). The JAK/STAT pathway has also been suggested to be involved in the modulation of glutamatergic neurotransmission (Raymond et al, 2011).…”