title: Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency.
abstract: Genetic defects in ammonia metabolism can produce irreversible damage of the developing CNS causing an impairment of cognitive and motor functions. We investigated alterations in behavior, synaptic plasticity and gene expression in the hippocampus and dorsal striatum of transgenic mice with systemic hyperammonemia resulting from conditional knockout of hepatic glutamine synthetase (LGS-ko). These mice showed reduced exploratory activity and delayed habituation to a novel environment. Field potential recordings from LGS-ko brain slices revealed significantly reduced magnitude of electrically-induced long-term potentiation (LTP) in both CA3-CA1 hippocampal and corticostriatal synaptic transmission. Corticostriatal but not hippocampal slices from LGS-ko brains demonstrated also significant alterations in long-lasting effects evoked by pharmacological activation of glutamate receptors. Real-time RT-PCR revealed distinct patterns of dysregulated gene expression in the hippocampus and striatum of LGS-ko mice: LGS-ko hippocampus showed significantly modified expression of mRNAs for mGluR1, GluN2B subunit of NMDAR, and A1 adenosine receptors while altered expression of mRNAs for D1 dopamine receptors, the M1 cholinoreceptor and the acetylcholine-synthetizing enzyme choline-acetyltransferase was observed in LGS-ko striatum. Thus, inborn systemic hyperammonemia resulted in significant deficits in novelty acquisition and disturbed synaptic plasticity in corticostriatal and hippocampal pathways involved in learning and goal-directed behavior.
authors.affiliation: Institute of Neural and Sensory Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany.|Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
authors.forename: Aisa N
authors.initials: AN
authors.lastname: Chepkova
authors.affiliation: Institute of Neural and Sensory Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany.|Institute of Clinical Neurosciences and Medical Psychology, Heinrich Heine University, D-40225 Düsseldorf, Germany.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Sergeeva
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Görg
authors.affiliation: Institute of Neural and Sensory Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany.
authors.forename: Helmut L
authors.initials: HL
authors.lastname: Haas
authors.affiliation: Institute of Neural and Sensory Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany.
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D005106:Exploratory Behavior; D005974:Glutamate-Ammonia Ligase / Q000172:deficiency* / Q000235:genetics; D006185:Habituation, Psychophysiologic; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D022124:Hyperammonemia / Q000151:congenital / Q000235:genetics* / Q000523:psychology*; D008099:Liver / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D017448:Receptors, Dopamine D2 / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D005974:Glutamate-Ammonia Ligase