The vulnerability of calretinin-containing hippocampal interneurons to temporal lobe epilepsy

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.

Connexin36 Expression in the Mammalian Retina: A Multiple-Species Comparison

“…CaR that specifically marks selective neuron populations in various areas of the central nervous sytem (Eyles et al, 2002; Ulfig, 2002; Grateron et al, 2003; Džaja et al, 2014; Hladnik et al, 2014; Tóth and Maglóczky, 2014) including the vertebrate retina (Völgyi et al, 1997; Gábriel and Witkovsky, 1998; Gábriel et al, 1999; Araki and Hamassaki-Britto, 2000). CaR has also been shown to be expressed by AII cells in a number of examined mammalian species.…”

HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations

“…Of particular interest, the selective vulnerability of multiple subsets of CR+ cells in the hippocampus may occur in a temporal-lobe epilepsy model, a good predictor of neuronal vulnerability to excitotoxicity. Those cells that remain exhibit pathologic dendritic varicosities and a loss of dendritic complexity and synapses, as a result of excitotoxic injury (Tóth et al 2010; Tóth and Maglóczky 2014). Patients with epilepsy can have fewer nNOS+ interneurons within CA1 (Leite et al 2002).…”

“…Hippocampal interneurons interact as part of a functional network and it is clear that the removal of even one cell type from the network can have drastic effects on information processing, pyramidal cell excitation, and consequent behavioral outcomes (Moga et al 2002; Dugladze et al 2007; Goldin et al 2007; Tóth et al 2010; Peng et al 2013; Long et al 2014; Lovett-Barron et al 2014; Lovett-Barron and Losonczy 2014; Tóth and Maglóczky 2014; Orbán-Kris et al 2015). Importantly, the susceptible nNOS+/NPY− interneurons of the stratum pyramidale and the stratum radiatum, PV+ cells of the stratum pyramidale, and SST+ interneurons of the stratum oriens form a microcircuit known to be involved in a complex feedback loop/input gating mechanism that regulates network synchronization within CA1 (Fig.…”

The enigmatic mossy cell of the dentate gyrus

“…LTP of the perforant path–granule cell synapse was reduced in mice lacking calretinin compared with wild-type mice 69 . Although intriguing, the study was limited by the constitutive nature of the knockout and the expression of calretinin in cells other than mossy cells (including a subtype of interneuron in the dentate gyrus 70 ). However, other methods have also shown that mossy cells may facilitate or even be required for LTP of the perforant path input to granule cells.…”

“…It has also been proposed that mossy cell-mediated excitation of granule cells is increased after insults that lead to TLE, causing hyperexcitability 1,104–106,111,112 . However, hyperexcitability could also be caused by a loss of HIPP cells 97 or calretinin-expressing interneurons 70 . Diverse changes in other aspects of the inhibitory control of granule cells 113 , including changes in the subunit composition of type A GABA receptors 114–116 , have led to the current consensus that a loss of mossy cells may contribute to TLE but is unlikely to be fully responsible for it.…”