[Abstract Title]. - Society for Neuroscience

Title: Decreased glutamate clearance by glutamate transporters contributes to abnormal
activation of NMDA receptors in the spinal substantia gelatinosa (SG) neurons of neuropathic
rats
Authors: *H.-R. WENG 1 , H. NIE 2 ;
1 Dept of Anesthesiolo, Univ. of TX, Houston, TX; 2 Anesthesiol. and Pain Med., Univ. of Texas
MD Anderson Cancer Ctr., Houston, TX
Abstract: Activation of NMDA receptors, which is a key step in the pathogenesis of pain,
depends on the spatiotemporal profile of glutamate in the synaptic cleft and extrasynaptic space.
The homeostasis of glutamate in the CNS is ensured by a family of glutamate transporters in the
plasma membrane of both glial cells and neurons. In this study, we asked if impaired glutamate
transporters contributed to the abnormal activation of NMDA receptors in spinal substantia
gelatinosa (SG) neurons of neuropathic rats. The expression of glutamate transporters was
examined by immunohistology. Activation of NMDA receptors was analyzed by recording
NMDA excitatory postsynaptic currents (EPSCs) of the spinal SG neurons evoked by graded
electrical stimulation of the dorsal root entry zone in L4-5 spinal slices taken from adult normal
and neuropathic rats on days 7-14 post-partial sciatic nerve ligation. Expression of glutamate
transporters in the spinal dorsal horn was downregulated in neuropathic rats. The peak latency
and duration of NMDA EPSCs in the spinal SG neurons were significantly greater in neuropathic
rats than in normal rats, although the NMDA amplitudes were not significantly different. This
abnormal activation of NMDA receptors could be simulated by pharmacological blockade of
glutamate transporters in normal rats. Limiting extracellular glutamate spillover in neuropathic
rats by adding 5% dextran to the perfusing solution resulted in shortening of the NMDA EPSC
duration, decay time, and peak latency, indicating that glutamate spillover contributed to the
abnormal activation of NMDA receptors in neuropathic rats. Dextran also increased the NMDA
amplitude in neuropathic rats, indicating that more synaptic NMDA receptors were activated by
the accumulated glutamate molecules inside the synaptic cleft owing to less glutamate spillover.
In contrast, perfusion of 5% dextran had only minimal effects on the NMDA EPSCs in normal
rats, indicating that glutamate spillover is minimal under normal conditions. These results
indicate that impaired glutamate transporters lead to abnormal activation of NMDA receptors in
neuropathic rats and suggest that repairing the damaged glutamate transporters may be a new
avenue for the management of pathological pain.
Supported by funds (to H.R.W.) provided by UT M. D. Anderson Cancer Center.
Disclosures: H. Weng , None; H. Nie, None.
Poster
242. Glial Neuronal Interactions: Glutamate and Calcium
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm