Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus

Abstract

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.

Down-regulation of the axonal polysialic acid–neural cell adhesion molecule expression coincides with the onset of myelination in the human fetal forebrain

“…In the human brain expression of PSA-NCAM was previously described in the fetal ganglionic eminence (Ulfig and Chan, 2004) and in the adult cerebral cortex (Arellano et al, 2002) and hippocampus (Ni Dhuill et al, 1999;Arellano et al, 2004). Presence of PSA-NCAM, as an embryonic form of NCAM, in the adult human brain was related to brain pathology, such as schizophrenia (Barbeau et al, 1995) and pituitary tumors (Trouillas et al, 2003).…”

Dysfunction of hippocampal interneurons in epilepsy

“…Loss of PV-positive neurons, especially those of the hilus, has been reported in human patients and animal models of epilepsy [9,28] . The loss of interneurons may lead to reduced inhibition of granule cells, thereby increasing the granule cell excitability and strengthening excitation in the dentate gyrus and other connected r e g i o n s [29] .…”

Chandelier Cells Control Excessive Cortical Excitation: Characteristics of Whisker-Evoked Synaptic Responses of Layer 2/3 Nonpyramidal and Pyramidal Neurons

“…An alternative model for epileptogenesis is that selective loss of chandelier cells, as commonly observed at epileptic foci (Williams et al, 1977;Ribak, 1985;Freund and Buzsaki, 1988;Marco et al, 1996;Arellano et al, 2004), is a crucial event that initiates epileptic activity (DeFelipe, 1999); however, this hypothesis, although intriguing, has not received significant attention because the functional role of chandelier cells in neuronal circuitry is unknown, and it is thus possible that loss of chandelier cells reflects simply a consequence of epileptic activity. Our in vivo results suggest that instead of being involved in processing and coding fast sensory information, chandelier cells may be reserved to oversee the balance of excitatory and inhibitory inputs over a large cortical area, and these cells increase their firing rate dramatically when excitation overpowers inhibition.…”

“…Because loss of chandelier cells is commonly and preferentially found at epileptic foci, it is proposed that they are functionally associated with epilepsy (Williams et al, 1977;Ribak, 1985;Freund and Buzsaki, 1988;Marco et al, 1996;Arellano et al, 2004). This view is supported by recent in vivo recordings from two morphologically identified chandelier cells, showing that these cells tend to fire action potentials shortly after synchronized activity of pyramidal neurons (Klausberger et al, 2003).…”