Why do high phenylalanine levels cause mental retardation? The key role of serotonin studied in hyperphenylalaninemic mice

Research project

Description

Dendritic branching alterations and the degree of dendritic spine maturation in frontal cortical areas are considered the most consistent anatomical correlates associated with mental retardation. In fact, morphological alterations of dendrites and dendritic spines are observed in the fronto-cortical areas of the most common syndromes related to mental retardation, such as Fragile-X or Down syndromes.
In a genetic mouse model of phenylketonuria (ENU2 mice), the most common inherited metabolic disorder associated with mental retardation, we have recently demonstrated the ability to recover morphological deficit in the medial Prefrontal Cortex ( mPFC ) through serotonergic treatment during the third postnatal week (PND14 -21). These data confirm the role of serotonin during development, but do not explain the molecular mechanisms by which this recovery occur. Thus, the objective of this project is to evaluate the molecular mechanisms underlying the recovery of morphological maturation of dendritic spines in neurons of layer V of the mPFC observed in ENU2 mice treated in the third postnatal week with a serotonergic compound. Among the candidates, the 5HT2A serotonin receptor that, through interaction with glutamatergic NMDA and AMPA receptors, plays an essential role in the synaptic maturation processes in frontal cortical areas induced by serotonin. We will analyze the levels of expression and distribution of 5HT2A receptor and NMDA (NR2A and NR2B subunits) and AMPA (Glu1 and Glu2/3 subunit) glutamate receptors in the mPFC of ENU2 mice after serotonergic treatment during the third postnatal week.
StatusActive
Effective start/end date1/1/10 → …

Funding

  • University of Rome, Sapienza

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Phenylalanine
Intellectual Disability
Serotonin
Dendritic Spines
Prefrontal Cortex
N-Methyl-D-Aspartate Receptors
Fragile X Syndrome
Phenylketonurias
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
AMPA Receptors
Serotonin Receptors
Genetic Models
Glutamate Receptors
Dendrites
Down Syndrome
Neurons