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The Journal of Neurophysiology Vol. 85 No. 4 April 2001, pp. 1533-1542
Copyright ©2001 by the American Physiological Society
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520
Patrylo, Peter R.,
Dennis D. Spencer, and
Anne Williamson.
GABA Uptake and Heterotransport Are Impaired in the Dentate Gyrus
of Epileptic Rats and Humans With Temporal Lobe Sclerosis. J. Neurophysiol. 85: 1533-1542, 2001. In vivo
dialysis and in vitro electrophysiological studies suggest that GABA
uptake is altered in the dentate gyrus of human temporal lobe
epileptics characterized with mesial temporal sclerosis (MTLE).
Concordantly, anatomical studies have shown that the pattern of
GABA-transporter immunoreactivity is also altered in this region. This
decrease in GABA uptake, presumably due to a change in the GABA
transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under several conditions, including elevations in [K+]o, which occurs
during seizures. Thus GABA transporters could contribute to seizure
termination and propagation through heterotransport. To test whether
GABA transport is compromised in both the forward (uptake) and reverse
(heterotransport) direction in the sclerotic epileptic dentate gyrus,
the physiological effects of microapplied GABA and nipecotic acid (NPA;
a compound that induces heterotransport) were examined in granule cells
in hippocampal slices from kainate (KA)-induced epileptic rats and
patients with temporal lobe epilepsy (TLE). GABA- and NPA-induced
responses were prolonged in granule cells from epileptic rats versus
controls (51.3 and 31.3% increase, respectively) while the conductance
change evoked with NPA microapplication was reduced by 40%.
Furthermore the ratio of GABA/NPA conductance, but not duration, was
significantly >1 in epileptic rats but not controls, suggesting a
compromise in transporter function in both directions. Similar changes
were observed in tissue resected from epileptic patients with medial
temporal sclerosis but not in those without the anatomical changes
associated with MTLE. These data suggest that the GABA transporter
system is functionally compromised in both the forward and reverse
directions in the dentate gyrus of chronically epileptic tissue
characterized by mesial temporal sclerosis. This alteration may enhance
inhibitory tone interically yet be permissive for seizure propagation
due to a decreased probability for GABA heterotransport during seizures.
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