Abstract
We studied group-I metabotropic glutamate (mGlu) receptors in Pahenu2 (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild-type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy.
Highlights
Phenylketonuria (PKU), one of the most common inherited inborn errors of metabolism, is caused by the deficiency of the enzyme phenylalanine hydroxylase (PAH), which catalyzes the conversion of the phenylalanine (Phe) into tyrosine
We examined whether the PKU phenotype was associated with changes in the expression of mGlu1α and mGlu5 receptors in brain regions that play key roles in cognitive function and motor programming
Group-I metabotropic glutamate (mGlu) receptors have been the focus of extensive investigation in animal models of intellectual disability (ID) and autism since Mark Bear, Kimberly Huber, and their Associates have shown that mGlu5 receptor-dependent long-term depression (LTD) is amplified in the hippocampus of Fmr1 knockout mice modeling Fragile-X syndrome
Summary
Phenylketonuria (PKU), one of the most common inherited inborn errors of metabolism, is caused by the deficiency of the enzyme phenylalanine hydroxylase (PAH), which catalyzes the conversion of the phenylalanine (Phe) into tyrosine. The clinical outcome of PKU is suboptimal, and earlytreated patients still exhibit lower intelligence quotient (IQ) and additional neuropsychiatric problems (Smith et al, 1990; DeRoche and Welsh, 2008; Burton et al, 2013; Nardecchia et al, 2015; Manti et al, 2016).
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