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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.
Highlights
Several reports suggest an association between autism and inherited metabolic diseases among which phenylketonuria (PKU), suggesting that autism spectrum disorders might represent the end result of a dysfunction caused by a metabolic block in the brain [1]
Since synaptic transmission is regulated by a plethora of molecules where cell-adhesion molecules are emerging as crucial players [8], we have studied the neuroligin/neurexin (NLGN/NRXN) pathway involved in the maturation of the inhibitory and excitatory synapses [9]
In order to assess whether immature spine morphology and cognitive impairments described for PKU in the ENU2 mice [6] reflect functionally a different cortical activity in comparison to parental controls, we have measured the spontaneous inhibitory postsynaptic currents and spontaneous excitatory postsynaptic currents from layer II/III of brain prefrontal cortex (pFC) by using whole-cell patch clamp recordings
Summary
Several reports suggest an association between autism and inherited metabolic diseases among which phenylketonuria (PKU), suggesting that autism spectrum disorders might represent the end result of a dysfunction caused by a metabolic block in the brain [1]. PKU is the prototypical human Mendelian disease (OMIM 261600; overall incidence of 1 in 10,000) resulting from impaired activity of phenylalanine hydroxylase (PAH), the enzyme necessary to convert phenylalanine (PHE) to tyrosine. This deficiency causes hyperphenylalaninemia (HPA), which is especially harmful for the brain during the first years of life, resulting in variable neurological and mental impairments [2,3,4]. Previous evidence from our group demonstrated that the accumulation of PHE in the brain of BTBR-Pahenu (ENU2) mice impairs protein levels and enzymatic activity of the tryptophan hydroxylase, the rate-limiting enzyme responsible for serotonin biosynthesis [5], and that the serotonin reduction in the brain causes cortical morphological alterations such as a reduction in the dendritic spine density and maturation [6]. Copy number variations and/or several single point mutations in the NLGN/NRXN synaptic pathway have been detected in association to neurodevelopmental disorders [11] including autism spectrum disorders [12,13,14,15,16,17]
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