Remodeling of neuronal circuitries in human temporal lobe epilepsy: Increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex

Abstract

Neuronal loss and axonal sprouting are the most typical histopathological findings in the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epileptogenesis. Also, little is known about the plasticity outside of the hippocampus. We investigated the immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n=25) and autopsy controls (n=7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurite outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-NCAM immunoreactivity was increased both in the inner and outer molecular layers of the dentate gyrus, compared with controls. The intensity of PSA-NCAM immunoreactivity in the inner molecular layer correlated with the duration of epilepsy, severity of hippocampal neuronal loss, density of mossy fiber sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of infragranular immunopositive neurons was increased twofold compared with controls, whereas in TLE patients with severe neuronal loss, the infragranular PSA-NCAM-positive cells were not present. In the hilus, the somata and tortuous dendrites of some surviving neurons were intensely stained in TLE. PSA-NCAM immunoreactivity was also increased in CA1 and in layer II of the rostral entorhinal cortex, where immunopositive neurons were surrounded by PSA-NCAM-positive fibers and puncta. Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the dentate gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.

Polysialic Acid Profiles of Mice Expressing Variant Allelic Combinations of the Polysialyltransferases ST8SiaII and ST8SiaIV

“…Thus, precise adjustment of polysialylation levels might be essential for the fine-tuning of NCAM-mediated interactions. Understanding the individual impact of the two polysialyltransferases ST8SiaII and ST8SiaIV in vivo provides the basis to unravel the mechanisms controlling the polySia pattern during development, plasticity, and aging of the nervous system, but also dur-ing the progression of polySia-expressing tumors (46), as well as in neurodegenerative and neuropsychiatric disorders (47)(48)(49)(50).…”

Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures

“…While the projection of GC axons (mossy fibers) to the ML is quite sparse in normal rodents (Claiborne et al, 1986;Ribak and Peterson, 1991;Sutula et al, 1998), it is remarkably augmented in animal models of TLE (reviewed in Houser, 1999), as well as in humans with this hippocampal epilepsy (deLanerolle et al, 1989;Sutula et al, 1989;Houser et al, 1990;Babb et al, 1991, Mikkonen et al, 1998. Because the majority of these "sprouted" supragranular mossy fibers terminate on GC dendrites (Okazaki et al, 1995;Wenzel et al, 2000;Buckmaster et al, 2002), they may increase the excitability of GCs and thus promote epileptogenesis (but see Longo and Mello, 1998;Nissinen et al, 2001).…”

“…The loss of these neurons and the resulting changes in hippocampal circuitry are considered the principal neuroanatomical basis of epileptogenesis (for review, see Houser, 1999). Because seizures in animal models can lead to both epilepsy and to neuroanatomical changes highly reminiscent of these observed in hippocampus of patients with TLE (deLanerolle et al, 1989;Sutula et al, 1989;Houser et al, 1990;Babb et al, 1991;Sloviter, 1991;Mathern et al, 1995;Mikkonen et al, 1998), it has been widely hypothesized that (1) hippocampal cell loss in the human is a consequence of previous seizure-induced injury, and (2) this seizure-induced injury plays a key role in the development of TLE. These hypotheses have been particularly important in considering the relationship of prolonged febrile seizures and subsequent temporal lobe epilepsy (Cendes et al, 1993;French et al, 1993).…”

In vitro ictogenesis and parahippocampal networks in a rodent model of temporal lobe epilepsy

“…Evidence obtained from humans and rodents indicates that epileptic hyperexcitability results from seizure-induced brain damage leading to (i) synaptic reorganization (Sutula et al, 1989;Mikkonen et al, 1998;Houser, 1999;Gorter et al, 2001), (ii) loss of specific interneuron subtypes (Bernard et al, 2000;Maglóczky and Freund, 2005) and (iii) alterations in GABAergic inhibition (Sloviter, 1987;Brooks-Kayal et al, 1998). The latter changes along with NMDA receptor upregulation have been reported in pilocarpine-treated parahippocampal areas such as the subiculum (Knopp et al, 2005;de Guzman et al, 2006), the EC (Kobayashi et al, 2003;Kumar and Buckmaster, 2006;Yang et al, 2006;de Guzman et al, 2008) and the lateral amygdala (LA) (Benini and Avoli, 2005).…”