5-Hydroxytryptophan during critical postnatal period improves cognitive performances and promotes dendritic spine maturation in genetic mouse model of phenylketonuria

Diego Andolina, David Conversi, Simona Cabib, Antonio Trabalza, Rossella Ventura, Stefano Puglisi-Allegra, Tiziana Pascucci

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19 Citations (Scopus)

Abstract

Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAH enu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14-21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.

Original languageEnglish
Pages (from-to)479-489
Number of pages11
JournalInternational Journal of Neuropsychopharmacology
Volume14
Issue number4
DOIs
Publication statusPublished - May 2011

Fingerprint

5-Hydroxytryptophan
Dendritic Spines
Phenylketonurias
Genetic Models
Serotonin
Brain
Prefrontal Cortex
Intellectual Disability
Tryptophan Hydroxylase
Pyramidal Cells
Therapeutics
Hydroxylation
Phenylalanine
Tryptophan
Critical Period (Psychology)
Spine

Keywords

  • Brain development
  • dendritic anomalies
  • medial prefrontal cortex
  • mental retardation
  • phenylketonuria
  • serotonin

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health

Cite this

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title = "5-Hydroxytryptophan during critical postnatal period improves cognitive performances and promotes dendritic spine maturation in genetic mouse model of phenylketonuria",
abstract = "Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAH enu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14-21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.",
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T1 - 5-Hydroxytryptophan during critical postnatal period improves cognitive performances and promotes dendritic spine maturation in genetic mouse model of phenylketonuria

AU - Andolina, Diego

AU - Conversi, David

AU - Cabib, Simona

AU - Trabalza, Antonio

AU - Ventura, Rossella

AU - Puglisi-Allegra, Stefano

AU - Pascucci, Tiziana

PY - 2011/5

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N2 - Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAH enu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14-21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.

AB - Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAH enu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14-21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.

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