Histological maturation of the neocortex in phenylketonuric rats

Cordero, María Elena; Trejo, Manuel; Colombo, Marta; Aranda, Verónica

doi:10.1016/0378-3782(83)90072-5

Cited by 21 publications

(15 citation statements)

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“…Notably, such changes usually escape standard neuropathologic evaluation and can only be proven by subtle quantitative analyses as performed in our study (25). In two animal models for PKU, dendritic development has been studied: In the neocortex of phenylketonuric rats, changes in the structural organization of the cerebral cortex and a decreased number of span and basilar processes of large pyramidal cells were found (11). Another study showed decreased synaptogenesis in the cerebral cortex …”

Section: Discussionmentioning

confidence: 99%

“…A more recent autopsy study of an untreated patient reports neuronal loss reduced size of neurons and decreased dendritic processes of Purkinje cells (10). Exposure of rodents to high doses of phenylalanine and pharmacological inhibition of phenylalanine hydroxylase induced changes in brain architecture, such as a decreased number and span of dendritic basilar processes of large pyramidal cells from deeper cortical cell layers (11). In PAH enu2 mice, hypomyelination and cortical gliosis have been demonstrated.…”

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confidence: 99%

“…Phenylalanine was reported to affect neuronal morphology and viability (11,25,26). In our primary neuronal cultures, we did not observe any changes in cell density, dendritic arborization, or dendritic length and diameter after 21 d of incubation.…”

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Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

et al. 2006

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Classical phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of PKU patients. PKU is neuropathologically characterized by reduced dendritic arborization, loss of synapses, and neurodegeneration. We investigated whether increased concentrations of phenylalanine cause reduced synaptic density and alter dendritic branching. We treated primary cortical neurons differentiated for 21 d in vitro with 5 mM phenylalanine in the presence of all essential amino acids. Immunocytochemical analysis of 12 and 21 d in vitro primary neurons revealed no changes of dendritic morphology or neuronal viability but a significant difference in synaptic density, suggesting that elevated concentrations of extracellular phenylalanine cause an impairment of synaptogenesis. Although impairment of cerebral energy metabolism has been identified as an important pathophysiological principal in many diseases, respiratory chain function has not been extensively studied in PKU before. We investigated whether phenylalanine inhibits respiratory chain complexes I-V. In vitro analysis revealed no inhibitory effect of phenylalanine on complexes I-V, but an inhibition of pyruvate kinase, a key enzyme of glycolysis, catalyzing the formation of pyruvate. Pyruvate kinase is part of the enzyme assay to investigate enzyme activity of mitochondrial complex V and it remains to be elucidated whether this finding is relevant in vivo. In conclusion, elevated concentrations of phenylalanine might be involved in mechanisms underlying impaired synaptogenesis in PKU, supporting the common therapeutic strategy to reduce phenylalanine concentrations in the brain to prevent neurodegeneration. (Pediatr Res 59: 544-548, 2006)

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Section: Discussionmentioning

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Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

et al. 2006

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“…Robain et al (25) reported a reduction in the number of dendritic branches in cerebellar Purkinje cells in the PKU rat. Cordero et al (26) found similar changes in the basal dendritic trees of large pyramidal neurons. Lacey (27) found spars and malformed dendritic spines on layer 5 pyramidal cells.…”

Section: Discussionmentioning

confidence: 75%

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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“…10 Algunos autores han propuesto que el exceso de fenilalanina afecta la viabilidad, la morfología y la excitabilidad neuronal. 3,[11][12][13][14] En modelos animales de fenilcetonuria se ha demostrado mielogénesis reducida, 15 disminución de la velocidad de conducción axonal así como disminución de la actividad de la Na+/ K+-ATPasa en las membranas sinápticas. 16 Existen evidencias que involucran al estrés oxidativo en la disfunción cerebral de la fenilcetonuria y también se ha demostrado que el exceso de fenilalanina produce daño al ADN en la corteza cerebral de ratas; [17][18][19][20][21] así mismo se han propuesto mecanismos neuropatogénicos relacionados con alteraciones en el proceso apoptósico.…”

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Resonancia magnética nuclear de encéfalo en pacientes con fenilcetonuria diagnosticada tardíamente

Jiménez-Pérez¹,

Gómez-Garza

Ruiz–García

et al. 2015

Acta Pediatr Mex

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9www.actapediatrica.org.mx artículo original Acta Pediatr Mex 2015;36:9-17. Resonancia magnética nuclear de encéfalo en pacientes con fenilcetonuria diagnosticada tardíamente RESUMEN Antecedentes: la fenilcetonuria clásica es una encefalopatía genética caracterizada por una inhabilidad de los individuos para metabolizar la fenilalanina, por lo que su concentración plasmática se eleva a niveles tóxicos. Clínicamente se manifiesta como irritabilidad, alteración del sueño, indiferencia al medio, crisis convulsivas, retraso del neurodesarrollo, conducta autista, agresividad y discapacidad intelectual.Objetivo: describir los hallazgos y cuantificar el coeficiente de difusión aparente en los estudios de imagen de resonancia magnética de cráneo, de pacientes con fenilcetonuria clásica diagnosticada tardíamente en el Instituto Nacional de Pediatría (México).Materiales y métodos: análisis retrospectivo de imágenes cerebrales obtenidas por resonancia magnética en pacientes con fenilcetonuria clásica. Se utilizó un magneto Signa Excite de 1.5 teslas con antena cerebral de ocho canales de arreglo en fase. Se midió el coeficiente de difusión aparente en la estación de trabajo Advantage Workstation 4.2p.Resultados: en los pacientes se observaron alteraciones en las sustancias blanca, gris, o ambas. En la sustancia blanca las lesiones hiperintensas en el área peritrigonal fueron las más frecuentes; se encontraron alteraciones bilaterales en la sustancia blanca frontal, temporal, occipital, subcortical y periventricular. Se observó disminución del coeficiente de difusión aparente en la sustancia blanca peritrigonal, occipital, cuerpo calloso, ganglios basales y cerebelo. Un paciente tenía dos quistes aracnoideos.Conclusión: todos los pacientes estudiados tuvieron las anormalidades características de la enfermedad en las imágenes de resonancia magnética. Los mecanismos causantes de las lesiones cerebrales en la fenilcetonuria, su distribución espacial y su evolución son poco conocidos y requieren de investigaciones posteriores.Palabras clave: fenilcetonuria, PKU, deficiencia de fenilalanina hidroxilasa, errores innatos del metabolismo, imagen de resonancia magnética, coeficiente de difusión aparente, ADC, discapacidad intelectual.

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Histological maturation of the neocortex in phenylketonuric rats

Cited by 21 publications

References 22 publications

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

Phenylalanine Reduces Synaptic Density in Mixed Cortical Cultures from Mice

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

Resonancia magnética nuclear de encéfalo en pacientes con fenilcetonuria diagnosticada tardíamente

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