The International Journal of Neuropsychopharmacology

  • The International Journal of Neuropsychopharmacology / Volume 14 / Issue 04 / May 2011, pp 479-489
  • © CINP and Cambridge University Press 2010 The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence <>. The written permission of Cambridge University Press must be obtained for commercial re-use.
  • DOI: (About DOI), Published online: 01 November 2010

Thematic Section: Consequences of Developmental Exposure to Drugs, Hormones or Altered Environment

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

Diego Andolinaa1a2, David Conversia1a2, Simona Cabiba1a2, Antonio Trabalzaa2, Rossella Venturaa2a3, Stefano Puglisi-Allegraa1a2 and Tiziana Pascuccia1a2 c1

a1 Dipartimento di Psicologia and Centro ‘Daniel Bovet’, ‘Sapienza’ University, Rome, Italy

a2 Santa Lucia Foundation, European Centre for Brain Research CERC, Rome, Italy

a3 Dipartimento di Scienze e Tecnologie Biomediche, Università dell'Aquila, L'Aquila, Italy


Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAHenu2 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.

(Received May 18 2010)

(Reviewed June 21 2010)

(Revised September 09 2010)

(Accepted September 16 2010)

(Online publication November 01 2010)


c1 Address for correspondence: Dr T. Pascucci, Dipartimento di Psicologia, ‘Sapienza’ University, via dei Marsi 78, 00185 Rome, Italy. Tel.: ++39-6-501703075 Fax: ++39-6-501703319. Email: