Abstract
This review focuses on the vulnerability of a special interneuron type—the calretinin (CR)-containing interneurons—in temporal lobe epilepsy (TLE). CR is a calcium-binding protein expressed mainly by GABAergic interneurons in the hippocampus. Despite their morphological heterogeneity, CR-containing interneurons form a distinct subpopulation of inhibitory cells, innervating other interneurons in rodents and to some extent principal cells in the human. Their dendrites are strongly connected by zona adherentiae and presumably by gap junctions both in rats and humans. CR-containing interneurons are suggested to play a key role in the hippocampal inhibitory network, since they can effectively synchronize dendritic inhibitory interneurons. The sensitivity of CR-expressing interneurons to epilepsy was discussed in several reports, both in animal models and in humans. In the sclerotic hippocampus the density of CR-immunopositive cells is decreased significantly. In the non-sclerotic hippocampus, the CR-containing interneurons are preserved, but their dendritic tree is varicose, segmented, and zona-adherentia-type contacts can be less frequently observed among dendrites. Therefore, the dendritic inhibition of pyramidal cells may be less effective in TLE. This can be partially explained by the impairment of the CR-containing interneuron ensemble in the epileptic hippocampus, which may result in an asynchronous and thus less effective dendritic inhibition of the principal cells. This phenomenon, together with the sprouting of excitatory pathway axons and enhanced innervation of principal cells, may be involved in seizure generation. Preventing the loss of CR-positive cells and preserving the integrity of CR-positive dendrite gap junctions may have antiepileptic effects, maintaining proper inhibitory function and helping to protect principal cells in epilepsy.
Highlights
Perisomatic inhibitory cells innervate the soma, axon initial segment or proximal dendrites of principal cells (Handelmann et al, Abbreviations: CA 1, 2, 3, regions of the Cornu Ammonis according to Lorente de No; CR, calretinin; TLE, temporal lobe epilepsy. 1981; Emson et al, 1982; Somogyi et al, 1983; Kosaka et al, 1985, 1987; Katsumaru et al, 1988; Seress et al, 1991, 1993a; Li et al, 1992; Ribak et al, 1993; Halasy et al, 1996) and control the output of principal cells (Arai et al, 1995; Freund and Buzsáki, 1996; Miles et al, 1996; Holmes and Levy, 1997)
Interneuron-selective cells were suggested to be important in the synchronization of dendritic inhibitory cells (Gulyás et al, 1996; Maglóczky and Freund, 2005; Chamberland et al, 2010; Tyan et al, 2014). This is supported by the fact that: (i) their dendrites are strongly connected by zona adherentiae and possibly by gap junctions in rats (Gulyás et al, 1992, 1993), which allows the synchronous activation of the connected cell population (Galarreta and Hestrin, 1999; Gibson et al, 1999); (ii) their dendrites often run parallel with each other in the human CA1 region, forming close contacts; zona adherentiae were identified in these segments at the electron microscopic level (Urbán et al, 2002), which is a characteristic structure to support the development of gap junctions (Kosaka and Hama, 1985); and (iii) the calbindin-containing dendritic inhibitory www.frontiersin.org interneurons are innervated by CR-positive inhibitory cells in both rats and humans (Figure 4; Gulyás et al, 1996; Tóth et al, 2010)
CONSEQUENCES OF THE VULNERABILITY OF CR-POSITIVE INTERNEURONS The alterations and/or sensitivity of different calcium-binding protein-containing interneurons in human TLE were discussed in several reports (Sloviter et al, 1991; Maglóczky et al, 2000; Wittner et al, 2001, 2002; van Vliet et al, 2004; Tóth et al, 2010)
Summary
Calretinin (CR) is a calcium-bindig protein, belonging to the calmodulin superfamily, which was shown to be present in many brain regions (Rogers, 1987; Faas et al, 2007).In the rodent hippocampus the majority of the CR-positive cells seem to be GABAergic interneurons (Jacobowitz and Winsky, 1991; Miettinen et al, 1992; Liu et al, 1996).They represent a distinct subpopulation of interneurons (Gulyás et al, 1992; Liu et al, 1996) with a negligible overlap with other calcium binding protein-containing interneurons— parvalbumin and calbindin—in rat and monkey (Miettinen et al, 1992; Rogers and Resibois, 1992; Seress et al, 1993b).Interneurons of the hippocampus can be divided into three main functional groups according to their role in the neuronal network (Freund and Buzsáki, 1996). This is supported by the fact that: (i) their dendrites are strongly connected by zona adherentiae and possibly by gap junctions in rats (Gulyás et al, 1992, 1993), which allows the synchronous activation of the connected cell population (Galarreta and Hestrin, 1999; Gibson et al, 1999); (ii) their dendrites often run parallel with each other in the human CA1 region, forming close contacts; zona adherentiae were identified in these segments at the electron microscopic level (Urbán et al, 2002), which is a characteristic structure to support the development of gap junctions (Kosaka and Hama, 1985); and (iii) the calbindin-containing dendritic inhibitory www.frontiersin.org interneurons are innervated by CR-positive inhibitory cells in both rats and humans (Figure 4; Gulyás et al, 1996; Tóth et al, 2010).
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