Morris - Coole / Epilepsia Prize

Mesial temporal lobe epilepsy (mTLE) is characterized by a complex cellular and functional pathology pattern. The relationship of individual pathogenic elements remains frequently elusive and their functional consequence is often unclear. Hippocampal sclerosis with segmental neurodegeneration and concomitant astrogliosis as pathologic hallmarks is the most frequent damage pattern. Infiltrates of adaptive and innate inflammatory cells including activated microglia represent striking observations in affected tissue and have only recently gained attention with respect to potential epileptogenic relevance. Aberrant microglialto-neuronal signaling contributes to impaired hippocampal excitation/inhibition balance, and therefore represents an intriguing potential pathophysiologic mechanism. Hippocampal biopsy specimens from patients with pharmacoresistant mTLE undergoing epilepsy surgery for seizure relief allow unique insights into these mechanisms. However, several obstacles, including sufficient tissue quality for functional analyses and the limited availability of adequate controls, challenge the use of human hippocampal biopsy tissue for research. Epilepsy is however a unique brain disease that allows functional testing of postoperative tissues together with histologic exploration. In their awarded publication, Roseti et al. report on excellent complementary electrophysiologic, biochemical, and histopathologic analyses to unravel the pathogenic role of the chemokine CX3CL1 and its receptor CX3CR1 in modulating c-aminobutyric acid (GABA)ergic function in human mTLE tissue. The chemokine fractalkine/CX3CL1 and its G protein– coupled receptor CX3CR1 have been suggested as critical for neuronal excitability modulation. This includes modifying (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-mediated currents, and modulation of long-term synaptic plasticity and (GABA)ergic currents. CX3CR1 is present in innate and adaptive immune cells including microglia and T lymphocytes, and it was suggested to play a role in status epilepticus–induced neuronal damage and is abundant in mTLE tissue. GABA receptor A (GABAAR) functional impairment is a prominent feature of mTLE. Loss of subtypes of interneurons, redistribution of their projections on pyramidal cells, rearrangements of GABAA receptors, modification of neuronal chloride homeostasis leading to depolarizing effects of GABA, and modifications of the functionality of GABAA receptors along sustained activation have been shown previously. In their report, Roseti et al. shed light on new mechanisms linking pathologic inflammation–related findings and GABAergic signaling. The present study was based on the finding that repetitive activation of GABAAR produces a use-dependent decrease (rundown) of the GABA-evoked currents (IGABA), which is markedly pronounced in neuronal tissue of patients with pharmacoresistant mTLE and epileptic rats. Before the publication by Roseti et. al., virtually no information was available on the modulation of GABAergic neurotransmission by CX3CL1 in concert with the expression of its receptor in mTLE, and on links with inflammation. This pathogenic aspect of mTLE is highly intriguing with respect to pathophysiologic mechanisms, has far-reaching therapeutic perspectives, and is difficult to address in human mTLE biopsy tissue. Roseti et al. took advantage of a highly elegant methodologic approach using a “microtransplantation” of membrane method, that is, Xenopus oocytes are injected with membranes from surgically resected human brain tissue. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy