Increased serum levels of glutamate in adult patients with autism

Abstract

Background

Precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the major role of glutamate in brain development, we have hypothesized that glutamatergic neurotransmission plays a role in the pathophysiology of autism. In this study, we studied whether amino acids (glutamate, glutamine, glycine, d-serine, and l-serine) related to glutamatergic neurotransmission are altered in serum of adult patients with autism.

Methods

We measured serum levels of amino acids in 18 male adult patients with autism and age-matched 19 male healthy subjects using high-performance liquid chromatography.

Results

Serum levels (mean = 89.2 μM, S.D. = 21.5) of glutamate in the patients with autism were significantly (t = − 4.48, df = 35, p < 0.001) higher than those (mean = 61.1 μM, S.D. = 16.5) of normal controls. In contrast, serum levels of other amino acids (glutamine, glycine, d-serine, l-serine) in the patients with autism did not differ from those of normal controls. There was a positive correlation (r = 0.523, p = 0.026) between serum glutamate levels and Autism Diagnostic Interview–Revised (ADI-R) social scores in patients.

Conclusions

The present study suggests that an abnormality in glutamatergic neurotransmission may play a role in the pathophysiology of autism.

Introduction

Autism is a neuropsychiatric disorder characterized by severe and sustained impairment in social interaction, deviance in communication, and patterns of behavior and interest that are restricted, stereotyped, or both (Volkmar and Pauls, 2003). Although genetic and environmental factors are implicated in the pathophysiology of autism, the precise mechanisms underlying the pathophysiology of this disorder remain to be determined (Volkmar and Pauls, 2003, Baron-Cohen and Belmonte, 2005, Polleux and Lauder, 2004, McDougle et al., 2005).

Glutamate, the major excitatory neurotransmitter in the brain, plays a major role in brain development, affecting neuronal migration, neuronal differentiation, axon genesis, and neuronal survival (Coyle et al., 2002). Accumulating evidence suggests that abnormalities in glutamatergic neurotransmission may play a role in the pathophysiology of autism (McDougle et al., 2005). First, cDNA microarray technology has demonstrated that the glutamate neurotransmitter system is abnormal in postmortem brain samples of autism (Purcell et al., 2001). The mRNA levels of genes, including excitatory amino acid transporter 1 (EAAT 1) and AMPA-type glutamate receptor, are significantly increased in the brain of autism, suggesting abnormalities of glutamatergic neurotransmission in the pathogenesis of this disorder (Purcell et al., 2001). Genetic studies have demonstrated the involvement of single nucleotide polymorphisms (SNPs) in the genes encoding both metabotropic and ionotropic glutamate receptors in autism (Jamain et al., 2002, Serajee et al., 2003). Furthermore, a strong association of autism with SNPs within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1), has been demonstrated, suggesting the potential etiological role of AGC1 in autism (Ramoz et al., 2004, Segurado et al., 2005). However, recent two studies using large samples did not confirm the association of SLC25A12 gene and autism, suggesting that the SLC25A12 gene is not a major contributor to genetic susceptibility of autism (Blasi et al., 2006, Rabionet et al., 2006).

Second, it has been reported that blood levels of glutamate are altered in patients with autism (Rolf et al., 1993, Moreno-Fuenmayor et al., 1996, Aldred et al., 2003). Rolf et al. (1993) have reported that plasma levels of glutamate in children (8–14-year-olds) with autism are significantly decreased compared to age-matched healthy controls. In contrast, Aldred et al. (2003) have reported that plasma levels of glutamate in patients (4–29 year-olds) with autism or Asperger's syndrome are significantly increased compared with controls. One of the reasons for such contradictory findings could be a difference in sample composition; the study by Aldred et al. (2003) incorporated a wider age range. Nonetheless, previous studies indicate alterations in the glutamatergic system expressed at the periphery level. The studies reporting on blood levels of glutamate in autistic patients present inconsistent results. Therefore, it is of great interest to examine whether levels of amino acids such as glutamate are altered in autistic patients.

Several lines of evidence suggest that d-serine, an endogenous co-agonist at the NMDA receptors, plays a role in the pathophysiology of schizophrenia, which is a neurodevelopmental disorder (Snyder and Ferris, 2000, Coyle and Tsai, 2004, Hashimoto et al., 2005a). We have previously reported that serum levels of d-serine are significantly decreased in patients with schizophrenia (Hashimoto et al., 2003, Yamada et al., 2005). However, to our knowledge, serum d-serine levels have never been investigated in relation to autism.

The purpose of the present study was, therefore, to examine whether individuals with autism have aberrant serum levels of d-serine as well as other amino acids (glutamate, glutamine, glycine, and l-serine) associated with glutamatergic neurotransmission. Furthermore, we also examined any relationship between amino acid levels and clinical symptoms in autistic patients.