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Int. J. Mol. Sci. 2017, 18(5), 941; doi:10.3390/ijms18050941

Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism

1
Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy
2
EBRI-European Brain Research Institute, 00143 Rome, Italy
3
Department of Psychology, “Daniel Bovet”, Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy
4
Foundation Santa Lucia, IRCCS, 00143 Rome, Italy
5
Department of Biology, University of Tor Vergata, 00133 Rome, Italy
6
Cell Biology and Neurobiology Institute, National Research Council, 00143 Rome, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Merlin G. Butler
Received: 28 February 2017 / Revised: 20 April 2017 / Accepted: 23 April 2017 / Published: 29 April 2017
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Abstract

Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pahenu2 (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders. View Full-Text
Keywords: neurotransmission; excitation and inhibition balance; cognitive delay; prefrontal cortex; neuroligins neurotransmission; excitation and inhibition balance; cognitive delay; prefrontal cortex; neuroligins
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MDPI and ACS Style

De Jaco, A.; Mango, D.; De Angelis, F.; Favaloro, F.L.; Andolina, D.; Nisticò, R.; Fiori, E.; Colamartino, M.; Pascucci, T. Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism. Int. J. Mol. Sci. 2017, 18, 941.

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