title: Disturbance of cultured rat neuronal network activity depends on concentration and ratio of leucine and alpha-ketoisocaproate: implication for acute encephalopathy of maple syrup urine disease.
abstract: Increased concentrations of leucine and its respective ketoacid alpha-ketoisocaproate (KIC) in plasma and cerebrospinal fluid are related to acute and reversible encephalopathy in patients with maple syrup urine disease. We studied electrophysiological properties of primary dissociated rat neurons at increased extracellular concentrations of leucine and KIC (1-10 mM). Spontaneous neuronal network activity was reversibly reduced or blocked by leucine as well as by KIC in a dose-dependent manner. Simultaneous incubation with both substances led to a minor inhibition compared to the effect of each substance alone. Neuronal resting potential, voltage dependent Na(+) (I(Na)) and K(+) (I(K)) currents, the GABA- and glycine-elicited membrane currents, and glutamate-induced intracellular Ca(2+) increase of single neurons, however, were unaffected by both substances. We conclude that acute neuronal network dysfunction in maple syrup urine disease is mainly based on an imbalance of the presynaptic glutamatergic/GABAergic neurotransmitter concentrations or their release.
authors.affiliation: Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Görtz
authors.forename: Hubertus
authors.initials: H
authors.lastname: Köller
authors.forename: Bernd
authors.initials: B
authors.lastname: Schwahn
authors.forename: Udo
authors.initials: U
authors.lastname: Wendel
authors.forename: Mario
authors.initials: M
authors.lastname: Siebler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D007651:Keto Acids / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism*; D008375:Maple Syrup Urine Disease / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D019579:Neocortex / Q000166:cytology; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism / Q000502:physiology; D051381:Rats
chemical_list: D003470:Culture Media; D007651:Keto Acids; D024642:Potassium Channels, Voltage-Gated; C013082:alpha-ketoisocaproic acid; D007930:Leucine