Hippocampal dendritic abnormalities in a rat model of phenylketonuria

Lacey, Daniel J.

doi:10.1002/ana.410160508

Cited by 11 publications

(3 citation statements)

References 13 publications

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“…It is the part of the brain with major neurological sensitivity, such that alterations in synthesis, storage, release, or inactivation of the excitatory or inhibitory amino acids could disrupt important neurological functions [Walsh and Emerich, 1988]. In PKU, there is clear evidence of dendritic abnormalities in the hippocampus [Lacey, 1984]. To date, similar neuropathologic studies have not been conducted in maternal PKU.…”

Section: Possible Theoretical Basis For Neuropsychological Effects Inmentioning

confidence: 99%

Developmental and neuropsychological outcome in children born to mothers with phenylketonuria

Waisbren

1999

Ment. Retard. Dev. Disabil. Res. Rev.

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Section: Possible Theoretical Basis For Neuropsychological Effects Inmentioning

confidence: 99%

Developmental and neuropsychological outcome in children born to mothers with phenylketonuria

Waisbren

1999

Ment. Retard. Dev. Disabil. Res. Rev.

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“…Glushakov et al (10) found that a high concentration of phenylalanine attenuated NMDA-activated currents in cultured hippocampal neurons. In vivo 31 P-MRS demonstrated abnormalities of cerebral energy metabolism in PKU, indicating a link between phenylalanine neurotoxicity and imbalances of cerebral energy metabolism (11). Lately, Horster et al (5) revealed that phenylalanine reduced synaptic density and simultaneously inhibited pyruvate kinase in mixed cortical cultures.…”

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confidence: 99%

Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons

Zhang

Yuan

et al. 2007

Pediatr Res

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Phenylketonuria (PKU) is characterized by a high concentration of phenylalanine, which can lead to mental retardation. One of the characteristic pathologic changes in untreated phenylketonuria patients is a reduction in the number of axons, dendrites, and synapses in the brain. This is thought to be due to the toxic effects of phenylalanine and/or its metabolites, however, the underlying mechanism remains unclear. In this study, we observed that phenylalanine reduced the number of dendrites and dendritic spines in cultured neurons. We further demonstrated that phenylalanine down-regulated Rac1, Cdc42, and RhoA mRNA and protein expression. Pull-down assays indicated that phenylalanine caused a decrease in Rac1/Cdc42 activity but increased RhoA activity. Expression of a dominant negative RhoA or treatment with a Rho-associated kinase specific inhibitor, Y-27632, partly inhibited the phenylalanine-induced decrease in dendrite numbers. In conclusion, we have demonstrated that phenylalanine affects the expression and activity of Rac1, Cdc42, and RhoA. Furthermore, RhoA signaling is involved in the inhibitory effect of phenylalanine on dendritic branching. These results may provide an important insight into the molecular mechanism underlying phenylalanine-induced abnormalities of dendrites, specifically in phenylketonuria neuronal injury. (Pediatr Res 62: 8-13, 2007) P henylketonuria (PKU) is one of the most frequent inborn disorders of amino acid metabolism. It is caused by a deficiency in phenylalanine hydroxylase (PAH), resulting in an accumulation of its upstream metabolite phenylalanine, mainly in brain tissue and the cerebrospinal fluid of PKU patients. Phenylalanine interferes with brain development and results in severe MR, microcephaly, epilepsy, and behavioral problems. These symptoms appear to be the direct consequence of neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction (1-5). Previous studies demonstrated that phenylalanine reduced Naϩ, Kϩ-ATPase and creatine kinase activity in rat brain (6 -8). Moreover, some neurotransmitters such as serotonin and dopamine were deficient in PKU animal models (9). Glushakov et al. (10) found that a high concentration of phenylalanine attenuated NMDA-activated currents in cultured hippocampal neurons. In vivo 31 P-MRS demonstrated abnormalities of cerebral energy metabolism in PKU, indicating a link between phenylalanine neurotoxicity and imbalances of cerebral energy metabolism (11). Lately, Horster et al. (5) revealed that phenylalanine reduced synaptic density and simultaneously inhibited pyruvate kinase in mixed cortical cultures. Our laboratory reported that phenylalanine and its metabolites caused neuronal cell apoptosis in vitro (12,13). Although these observations demonstrate that phenylalanine is probably the main causative agent of brain injury in PKU, the pathophysiological mechanisms of its actions in brain injury are multiple and not fully understood.As dendrites are the site of most synaptic c...

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“…Applications of the Golgi methods to the brains of PKU patients,~ and in animal models of PKU, [8][9][10][11][12] have shown alterations of neuronal and dendritic architecture that may account for the retardation and seizures. We have recently studied the brain of a 4month-old child with the maternal PKU syndrome, using routine and Golgi histologic techniques.…”

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confidence: 99%

Abnormal Cerebral Cortical Neurons in a Child With Maternal PKU Syndrome

Lacey

Terplan

1987

J Child Neurol

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A child born to a phenylketonuric (PKU) woman not on dietary treatment was microcephalic and had congenital heart and other physical anomalies consistent with the maternal PKU syndrome. After a repeat cardiac catherization at 3 months of age, he suffered an embolic left cerebral infarct and seizures. He was found by his mother dead in bed at 4 months of age; general autopsy revealed Klebsiella sepsis and pneumonia. Neuropathologic studies of the right cerebral hemisphere showed neuronal loss of the third cortical layer; Golgi studies revealed persistently immature cortical pyramidal cell somata and dendritic spines. This is the first report of specific neuronal abnormalities in a child with the maternal PKU syndrome and may, in part, account for the clinical features of microcephaly, mental retardation, and seizures seen in affected children.

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Hippocampal dendritic abnormalities in a rat model of phenylketonuria

Cited by 11 publications

References 13 publications

Developmental and neuropsychological outcome in children born to mothers with phenylketonuria

Developmental and neuropsychological outcome in children born to mothers with phenylketonuria

Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons

Abnormal Cerebral Cortical Neurons in a Child With Maternal PKU Syndrome

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