Loss of cholecystokinin-containing terminals in temporal lobe epilepsy.
Altered GABA-mediated inhibition is proposed to play a role in the pathogenesis of epilepsy. Previous studies have demonstrated a loss of somatostatin-containing GABAergic interneurons innervating granule cells in epileptic animals. However, the reorganization of synapses between interneurons and granule cells has not been investigated. We studied synapse organization in an animal model of temporal lobe epilepsy (TLE) using continuous hippocampal stimulation. The distribution of axon terminals and inhibitory synapses on granule cell dendrites was studied using a combination of immunohistochemistry and pre-embedding electron microscopy techniques. A whole-cell patch-clamp technique was applied to study the functional changes in GABAergic input from different interneurons. In epileptic animals, the density of cholecystokinin (CCK)-immunoreactive (IR) fibers and α2 subunit containing GABAA receptors in the inner molecular layer of the dentate gyrus was reduced. Quantitative immuno-electron microscopy study revealed that the ratio of CCK-containing symmetric synapses to the total symmetric synapses was reduced. The frequency of GABAergic synaptic currents (sIPSC) was decreased and their amplitude was increased. The inhibitory effect of the activation of cannabinoid 1 (CB1) receptors was also reduced in epileptic animals. Isolation of CCK- and parvalbumin (PV)-containing GABAergic inputs by N- and P/Q-type calcium channel blockers respectively suggested that GABA release from CCK-containing interneurons was selectively reduced in epileptic rats. This study found that there was a loss of CCK-containing GABAergic synapses to granule cells both morphologically and functionally. These studies add to our understanding of the mechanisms that contribute to altering GABAergic inhibition of granule cells in TLE.
Department of Neurology, University of Virginia, Health Sciences Center, PO Box 800394, Charlottesville, VA 22908, USA; Department of Psychology, University of Virginia, PO Box 400400, Charlottesville, VA 22904, USA.
Chengsan
C
Sun
Department of Neurology, University of Virginia, Health Sciences Center, PO Box 800394, Charlottesville, VA 22908, USA.
Jianli
J
Sun
Department of Psychology, University of Virginia, PO Box 400400, Charlottesville, VA 22904, USA.
Alev
A
Erisir
Department of Neurology, University of Virginia, Health Sciences Center, PO Box 800394, Charlottesville, VA 22908, USA; Department of Neuroscience, PO Box 801392, Charlottesville, VA 22908, USA. Electronic address: jk8t@virginia.edu.
Jaideep
J
Kapur
D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D007395:Interneurons / Q000502:physiology*; D008297:Male; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D021122:Protein Subunits; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin
Cholecystokinin-containing symmetric synapses; Dentate gyrus; Epilepsy; GABAergic interneuron; Spontaneous inhibitory postsynaptic currents