Chronic Epileptogenic Cellular Alterations in the Limbic System After Status Epilepticus

Abstract

Summary: Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons within the hilar region of the dentate gyrus, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of y-aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABA, receptors in chronically epileptic animals. In addition, the pharmacological properties of GABA, receptors in Status epilepticus (SE) is a severe and debilitating prolonged seizure that lasts for 30 min or longer and is frequently associated with significant acute mortality as well as long-term morbidity. In addition to the short-term impact of an episode SE on the anatomy and function of the CNS, there are also devastating long-term consequences. One of the most prevalent of these is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. This association has been exploited experimentally in the development of animal models of temporal lobe epilepsy (TLE). Several post-SE epileptic animals are quite different compared to controls. In particular, GABA, receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of a 1 subunits of the GABA, receptor relative to other a subunits in DGCs of post-SE epileptic animals. These GABA, receptor alterations precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc-containing "sprouted" mossy fiber terminals innervating the proximal dendrites of DGCs in the post-SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block "epileptic" zinc-sensitive GABA, receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propens...

The anti‐epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA‐ and glycine‐gated currents

“…In contrast, the data on zinc are remarkable when confronted to the possibility that the hyperexcitability of the epileptic hippocampus may be associated with circuit and cellular alterations involving changes both in the subunit expression pattern of GABA A receptors in dentate granule cells (DGC) and in sprouting of zinc-containing DGC axons back onto the inner molecular layer of the dentate gyrus. Indeed, a`sprouted mossy ®bre/zinc-sensitive GABA receptor' hypothesis was recently proposed (Coulter, 1999;. This theory is based on two principal epileptogenic phenomena.…”

Reduced Excitatory Drive onto Interneurons in the Dentate Gyrus after Status Epilepticus

“…Numerous alterations occur in hippocampal circuitry after SE, producing remodeled networks with properties significantly different from normal brain (Coulter, 1999;Sloviter, 1999). Many pathological alterations produced during epileptogenesis might disinhibit hippocampal circuitry, including changes in GABA A receptor subunit composition or properties (Bühl et al, 1996;Kapur and Macdonald, 1997;Brooks-Kayal et al, 1998;Macdonald and Kapur, 1999), death of GABAergic interneurons (Obenaus et al, 1993;Houser and Escaplez, 1996), changes in receptor-mediated regulation of GABAergic neurotransmission (Haas et al, 1996;Mangan and Lothman, 1996;Bausch and Chavkin, 1997), or loss of excitatory synaptic input onto GABAergic interneurons (Sloviter, 1991;Bekenstein and Lothman, 1993).…”

Inhibition of Excitatory Synaptic Transmission in Hippocampal Neurons by Levetiracetam Involves Zn2+-Dependent GABA Type A Receptor–Mediated Presynaptic Modulation

“…Zn 21 is an endogenous modulator of neuronal excitability that is at particularly high levels at mossy fiber synapses, with released Zn 21 able to modulate both glutamate and GABA A receptors (Sensi et al, 2009). Both Zn 21 -containing mossy fiber terminals and GABAergic transmission show significant changes in the epileptic brain (Coulter, 1999(Coulter, , 2000Rigo et al, 2002), making them important neuromodulators to consider when investigating anticonvulsant drug actions.…”

“…The interactions between LEV and Zn 21 may be clinically important, when considering the hippocampal hyperexcitability and altered synaptic circuits in temporal lobe epilepsy (Coulter, 1999(Coulter, , 2000. In both human temporal lobe epilepsy and in animal models, there is a marked sprouting of mossy fiber terminals to innervate new targets in the inner molecular layer of the dentate gyrus.…”