Brain Advance Access published online on May 26, 2008
Brain, doi:10.1093/brain/awn095
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Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy
1Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, 2Institute for Neurophysiology, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin and 3Department of Neurology, Friedrich-Schiller-University, Erlanger Allee 101, 07745 Jena, Germany
Correspondence to:
Joachim Behr, Dept. of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany E-mail: joachim.behr{at}charite.de
Clinical and experimental evidence suggest that the subiculum plays an important role in the maintenance of temporal lobe seizures. Using the pilocarpine-model of temporal lobe epilepsy (TLE), the present study examines the vulnerability of GABAergic subicular interneurons to recurrent seizures and determines its functional implications. In the subiculum of pilocarpine-treated animals, the density of glutamic acid decarboxylase (GAD) mRNA-positive cells was reduced in all layers. Our data indicate a substantial loss of parvalbumin-immunoreactive neurons in the pyramidal cell and molecular layer whereas calretinin-immunoreactive cells were predominantly reduced in the molecular layer. Though the subiculum of pilocarpine-treated rats showed an increased intensity of GAD65 immunoreactivity, the density of GAD65 containing synaptic terminals in the pyramidal cell layer was decreased indicating an increase in the GAD65 intensity of surviving synaptic terminals. We observed a decrease in evoked inhibitory post-synaptic currents that mediate dendritic inhibition as well as a decline in the frequency of miniature inhibitory post-synaptic currents (mIPSCs) that are restricted to the perisomatic region. The decrease in mIPSC frequency (–30%) matched with the reduced number of perisomatic GAD-positive terminals (–28%) suggesting a decrease of pre-synaptic GABAergic input onto pyramidal cells in epileptic animals. Though cell loss in the subiculum has not been considered as a pathogenic factor in human and experimental TLE, our data suggest that the vulnerability of subicular GABAergic interneurons causes an input-specific disturbance of the subicular inhibitory system.
Key Words: subiculum; temporal lobe epilepsy; pilocarpine; GABA; GAD
Abbreviations: ACSF, artificial cerebrospinal fluid; CR-IR, calretinin-immunoreactive; eIPSCs, evoked inhibitory post-synaptic currents; EPSPs, excitatory post-synaptic potential; GAD, glutamic acid decarboxylase; PFA, paraformaldehyde; PV-IR, parvalbumin-immunoreactive; RMP, resting membrane potential; TLE, temporal lobe epilepsy
Received December 10, 2007. Revised April 7, 2008. Accepted April 23, 2008.