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

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.

Comparison of the Metabolic Profiles in the Plasma and Urine Samples Between Autistic and Typically Developing Boys: A Preliminary Study

“…Although different discriminating metabolites were found in plasma and urine samples, results of the metabolic pathway analysis revealed that perturbations in pathways corresponding to taurine and hypotaurine metabolism, phenylalanine metabolism and arginine and proline metabolism could be found in both of the plasma and urine samples. The association of ASD and phenylketonuria (PKU), a disease induced by deficiency in the metabolism of phenylalanine, has been well-documented, and children with PKU often show some autistic-like behavior (74)(75)(76). Significant differences in urine and plasma levels of phenylalanine have also been found to be associated with ASD in several independent previously published studies (9,(77)(78)(79)(80)(81)(82), although some of these results were contradictory, all their data points to the perturbation of phenylalanine metabolism in ASD.…”

The neuroligins and the synaptic pathway in Autism Spectrum Disorder

“…Similarly, NLGN3 KO mice exhibited a cell type-specific imbalance between synaptic inhibition and excitation in the nucleus accumbens (Rothwell et al, 2014), while in the hippocampus a strong E/I imbalance in the CA2 region (Modi et al, 2019) and reduced gamma oscillations in the CA1 area (Polepalli et al, 2017) were observed. Interestingly, we observed a shift in the E/I balance toward inhibition, accompanied by higher levels of NLGN1 and NLGN2, in the prefrontal cortex of BTBR-Pah enu2 (ENU2) mice, an animal model of phenylketonuria (PKU), a metabolic disease with a welldocumented association with ASD (De Jaco et al, 2017).…”

Transient Cognitive Impairment in Epilepsy

“…Not surprisingly, the potentiation of GABA signaling is a prime pharmacological target that can result in a rescue of the phenotype (Lewine et al, 1999; Tuchman and Rapin, 2002; Levisohn, 2007; Gatto and Broadie, 2010; Bolton et al, 2011; Pizzarelli and Cherubini, 2011; Gilby and O’Brien, 2013; Tuchman, 2013; Cellot and Cherubini, 2014; Jeste and Tuchman, 2015; Buckley and Holmes, 2016). In contrast, other studies suggest that blocking the response to GABA can ameliorate cognitive impairment such as in Down syndrome (Kleschevnikov et al, 2004; Fernandez et al, 2007; Belichenko et al, 2009), in Rett syndrome (Dani et al, 2005; Dani and Nelson, 2009), in Angelman syndrome (Mabb et al, 2011) and in phenylketonuria (De Jaco et al, 2017). These opposing scenarios could be partly explained by the fact that GABA response polarity is not univocal, but it is determined by intracellular Cl − concentration, which in turn is finely regulated by the interplay of leak channels and specific co-transporters (NKCC1 and KCC2; Kaila et al, 2014; Miles et al, 2012; Viitanen et al, 2010; Löscher et al, 2013).…”