Abstract
Increased concentrations of leucine and its respective ketoacid α-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+ (INa) and K+ (IK) currents, the GABA- and glycine-elicited membrane currents, and glutamate-induced intracellular Ca2+ 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.
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Abbreviations
- BCAA:
-
branched-chain amino acid
- BCKA:
-
branched-chain keto acid
- DF:
-
depolarization frequency
- dF:
-
difference of fluorescence ratios
- DIV:
-
days in vitro
- INa,:
-
sodium membrane current
- IK:
-
potassium membrane current
- KIC:
-
α-ketoisocaproate
- MSUD:
-
maple syrup urine disease
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We thank Dr. Sascha Mager for helpful discussions and Brigida Ziegler for expert technical assistance.
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Supported by grants of the Forschungskommission der Heinrich-Heine Universität Düsseldorf, the Ministerium des Landes Nordrhein Westfalen (Biochip Initiative) and the SHS-International (Germany).
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Görtz, P., Köller, H., Schwahn, B. et al. Disturbance of Cultured Rat Neuronal Network Activity Depends on Concentration and Ratio of Leucine and α-Ketoisocaproate: Implication for Acute Encephalopathy of Maple Syrup Urine Disease. Pediatr Res 53, 320–324 (2003). https://doi.org/10.1203/01.PDR.0000047521.50656.16
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DOI: https://doi.org/10.1203/01.PDR.0000047521.50656.16
