Brain Advance Access originally published online on October 8, 2003
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Brain, Vol. 127, No. 1, 45-64, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh004
Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus
1 Departamento de Neuroanatomía y Biología Celular, Instituto Cajal, CSIC and 2 Departamento de Neurocirugía, Hospital de la Princesa, Madrid, Spain
Correspondence to: Dr J. DeFelipe or A. Muñoz, Instituto Cajal, CSIC, Av/ Doctor Arce 37, 28002 Madrid, Spain. E-mail: defelipe{at}cajal.csic.es
Impairment of GABA-mediated inhibition is one of the main hypotheses invoked to explain seizure activity, both in experimental models and in human epilepsy. We have studied the distribution and the neurochemical characteristics of certain GABAergic circuits in the normal and epileptic human sclerotic hippocampal formation. We have focused our attention mainly on chandelier cells because, together with basket cells, they are considered to have powerful effects on spike generation. Chandelier cells represent a unique type of interneuron whose axon terminals (Ch-terminals) form synapses with the axon initial segments of cortical pyramidal cells and granular cells of the dentate gyrus. Different neurochemical subpopulations of chandelier cells have been identified by immunocytochemistry, mainly in the neocortex. Markers for Ch-terminals include the GABA transporter 1 (GAT-1), the polysialylated form of the cell-surface glycoprotein neural cell adhesion molecule (PSA-NCAM) and the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB). In the normal hippocampal formation, GAT-1- and PV-immunoreactive (-ir) Ch-terminals were identified in the granular and polymorphic layers of the dentate gyrus, in the strata pyramidale and oriens of the CA fields, and in the pyramidal layer of the subicular complex. In addition, and in contrast to the hippocampus and dentate gyrus, subsets of Ch-terminals in the upper pyramidal layer of the normal subiculum express CB and PSA-NCAM. The sclerotic hippocampus of epileptic patients presented an impressive morphological and neurochemical reorganization of Ch-terminals and basket formations. This was apparent in the dentate gyrus and hippocampal formation, but not in the subiculum, which appeared to remain unaltered. Principally, numerous and more complex PV- and CB-ir Ch-terminals, as well as dense PV-ir basket formations, appeared in some hippocampal segments, whereas in other regions there was a lack of labelled elements. These changes varied considerably not only between different patients, but also within different hippocampal fields in a given patient. In general, the changes were not correlated with the clinical characteristics or degree of histopathological alterations observed in the patients, such as granular cell dispersion, neuron loss and proliferation of mossy fibres. However, some surviving neurons in the regions adjacent to the areas of neuron loss were consistently innervated by dense basket formations and complex Ch-terminals. These results indicate that, in the human epileptic hippocampus, GABAergic circuits are more highly modified than previously thought. When considered along with other extrahippocampal alterations, we suggest that these changes are important in the pathophysiology of temporal lobe epilepsy associated with hippocampal sclerosis.
Key Words: epilepsy; interneurons; inhibition; calcium-binding proteins; GABA transporter
Abbreviations: AIS = axon initial segment; CB = calbindin; Ch-terminal: chandelier cell axon terminal; GAT-1 = GABA transporter 1; ir = immunoreactive; NeuN = neuron-specific nuclear protein; PSA-NCAM = polysialylated neural cell adhesion molecule; PV = parvalbumin
Received March 25, 2003. Revised May 28, 2003. Accepted July 17, 2003.
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