Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy

• Published in: Journal of cellular and molecular medicine Vol. 12; no. 6b; pp. 2848 - 2866
• Main Authors: Eichler, Sabrina A., Kirischuk, Sergei, Jüttner, René, Schafermeier, Philipp K., Legendre, Pascal, Lehmann, Thomas‐Nicolas, Gloveli, Tengis, Grantyn, Rosemarie, Meier, Jochen C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2008; John Wiley & Sons, Inc
• Subjects: Action Potentials; Adult; Amino acids; Animals; Annealing; Brain; Calcium Signaling; Cell culture; Chlorides - metabolism; Cloning; Dendrites - metabolism; Depolarization; Drug resistance; Epilepsy; Epilepsy, Temporal Lobe - pathology; Epilepsy, Temporal Lobe - physiopathology; Equilibrium; Excitatory Postsynaptic Potentials; Excitotoxicity; Experiments; E‐I balance; Female; gamma-Aminobutyric Acid - metabolism; Gene expression; Glutamatergic transmission; Glycine - metabolism; glycine receptor; Glycine receptors; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Humans; inhibition; K Cl- Cotransporters; KCC2; Male; Middle Aged; Neurons; Neurons - metabolism; Neurons - pathology; Neurotoxins - metabolism; Neurotransmitters; Potassium chloride; Potassium-chloride cotransporter; Protein synthesis; Ratios; Rats; Rats, Wistar; Receptor, trkB - metabolism; Receptors, Glutamate - metabolism; Receptors, Glycine - metabolism; RNA editing; Symporters - metabolism; synapse elimination; Synaptic Transmission - physiology; Temporal lobe; tonic inhibition; TrkB receptors; γ-Aminobutyric acid; United States > US
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2008.00357.x

An increasing number of epilepsy patients are afflicted with drug‐resistant temporal lobe epilepsy (TLE) and require alternative therapeutic approaches. High‐affinity glycine receptors (haGlyRs) are functionally adapted to tonic inhibition due to their response to hippocampal ambient glycine, and their synthesis is activity‐dependent. Therefore, in our study, we scanned TLE hippocampectomies for expression of haGlyRs and characterized the effects mediated by these receptors using primary hippocampal neurons. Increased haGlyR expression occurred in TLE hippocampi obtained from patients with a severe course of disease. Furthermore, in TLE patients, haGlyR and potassium chloride cotransporter 2 (KCC2) expressions were inversely regulated. To examine this potential causal relationship with respect to TLE histopathology, we established a hippocampal cell culture system utilising tonic inhibition mediated by haGlyRs in response to hippocam‐pal ambient glycine and in the context of a high Cl equilibrium potential, as is the case in TLE hippocampal neurons. We showed that hypoactive neurons increase their ratio between glutamatergic and GABAergic synapses, reduce their dendrite length and finally undergo excitotoxicity. Pharmacological dissection of the underlying processes revealed ionotropic glutamate and TrkB receptors as critical mediators between neuronal hypoactivity and the emergence of these TLE‐characteristic histopathological signs. Moreover, our results indicate a beneficial role for KCC2, because decreasing the Cl− equilibrium potential by KCC2 expression also rescued hypoactive hippocampal neurons. Thus, our data support a causal relationship between increased haGlyR expression and the emergence of histopathological TLE‐characteristic signs, and they establish a pathophysiological role for neuronal hypoactivity in the context of a high Cl− equilibrium potential.