Increased serum levels of glutamate in adult patients with autism

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 microM, 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 microM, 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.

[1]  F. Serajee,et al.  The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism , 2003, Journal of medical genetics.

[2]  K. Grotemeyer,et al.  Serotonin and amino acid content in platelets of autistic children , 1993, Acta psychiatrica Scandinavica.

[3]  Patrick R Hof,et al.  Neuropathological findings in autism. , 2004, Brain : a journal of neurology.

[4]  S H Snyder,et al.  Novel neurotransmitters and their neuropsychiatric relevance. , 2000, The American journal of psychiatry.

[5]  R. Riikonen Neurotrophic Factors in the Pathogenesis of Rett Syndrome , 2003, Journal of child neurology.

[6]  J. Licinio,et al.  Autoimmunity in autism , 2002, Molecular Psychiatry.

[7]  A. Couteur,et al.  Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders , 1994, Journal of autism and developmental disorders.

[8]  W. Goodman,et al.  The Yale-Brown Obsessive Compulsive Scale. II. Validity. , 1989, Archives of general psychiatry.

[9]  E. Hollander,et al.  An open trial of divalproex sodium in autism spectrum disorders. , 2001, The Journal of clinical psychiatry.

[10]  F. Polleux,et al.  Toward a developmental neurobiology of autism. , 2004, Mental retardation and developmental disabilities research reviews.

[11]  B. Meldrum The role of glutamate in epilepsy and other CNS disorders , 1994, Neurology.

[12]  A. Plioplys Autism: electroencephalogram abnormalities and clinical improvement with valproic acid. , 1994, Archives of pediatrics & adolescent medicine.

[13]  R. Tuchman,et al.  Epilepsy in autism , 2002, The Lancet Neurology.

[14]  Kenji Hashimoto,et al.  Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. , 2003, Archives of general psychiatry.

[15]  W. Goodman,et al.  The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. , 1989, Archives of general psychiatry.

[16]  H. Jyonouchi,et al.  Innate Immunity Associated with Inflammatory Responses and Cytokine Production against Common Dietary Proteins in Patients with Autism Spectrum Disorder , 2002, Neuropsychobiology.

[17]  A. Buss,et al.  The aggression questionnaire. , 1992, Journal of personality and social psychology.

[18]  Kenji Hashimoto,et al.  Dysfunction of Glia-Neuron Communication in Pathophysiology of Schizophrenia , 2005 .

[19]  Andrew Calder,et al.  Acquired theory of mind impairments in individuals with bilateral amygdala lesions , 2003, Neuropsychologia.

[20]  S. Baron-Cohen,et al.  Autism: a window onto the development of the social and the analytic brain. , 2005, Annual review of neuroscience.

[21]  M. Gill,et al.  Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. , 2005, The American journal of psychiatry.

[22]  T. Toyo’oka,et al.  Simultaneous determination of D- and L-serine in rat brain microdialysis sample using a column-switching HPLC with fluorimetric detection. , 2004, Biomedical chromatography : BMC.

[23]  Kenji Hashimoto,et al.  Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naive schizophrenic patients , 2005, BMC psychiatry.

[24]  Samantha A. Stewart The effects of benzodiazepines on cognition. , 2005, The Journal of clinical psychiatry.

[25]  J. Pevsner,et al.  Postmortem brain abnormalities of the glutamate neurotransmitter system in autism , 2001, Neurology.

[26]  H. Cohly,et al.  Immunological findings in autism. , 2005, International review of neurobiology.

[27]  J. Coyle,et al.  The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia , 2004, Psychopharmacology.

[28]  H. Manji,et al.  Signaling: cellular insights into the pathophysiology of bipolar disorder , 2000, Biological Psychiatry.

[29]  S. R. Wickramasinghe,et al.  Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Jyonouchi,et al.  Dysregulated Innate Immune Responses in Young Children with Autism Spectrum Disorders: Their Relationship to Gastrointestinal Symptoms and Dietary Intervention , 2005, Neuropsychobiology.

[31]  B. Baethge,et al.  Excitatory amino acids, TNF‐α , and chemokine levels in synovial fluids of patients with active arthropathies , 2004, Clinical and experimental immunology.

[32]  E. Bacchelli,et al.  SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample , 2006, European Journal of Human Genetics.

[33]  I. Pye,et al.  STUDIES OF THE INTER‐RELATIONSHIP BETWEEN CEREBROSPINAL FLUID AND PLASMA AMINO ACID CONCENTRATIONS IN NORMAL INDIVIDUALS , 1977, Journal of neurochemistry.

[34]  Barbie Zimmerman-Bier,et al.  Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. , 2005, The Journal of pediatrics.

[35]  F. Wiesel,et al.  Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers , 1988, Biological Psychiatry.

[36]  D. Chuang Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? , 2004, Critical reviews in neurobiology.

[37]  T. Bourgeron,et al.  Linkage and association of the glutamate receptor 6 gene with autism , 2002, Molecular Psychiatry.

[38]  K. Hashimoto,et al.  Identification of Multiple Serine Racemase (SRR) mRNA Isoforms and Genetic Analyses of SRR and DAO in Schizophrenia and d-Serine Levels , 2005, Biological Psychiatry.

[39]  Dennis S. Charney,et al.  Neuropsychopharmacology : The Fifth Generation of Progress , 2002 .

[40]  Eden R Martin,et al.  Lack of association between autism and SLC25A12. , 2006, The American journal of psychiatry.

[41]  R. Jones,et al.  Recognition of Faux Pas by Normally Developing Children and Children with Asperger Syndrome or High-Functioning Autism , 1999, Journal of autism and developmental disorders.

[42]  T. Kemper,et al.  Neuropathology of infantile autism. , 1998, Journal of neuropathology and experimental neurology.

[43]  F. Volkmar,et al.  Seizure disorders in autism. , 1990, Journal of the American Academy of Child and Adolescent Psychiatry.

[44]  L. Borjas,et al.  Plasma excitatory amino acids in autism. , 1996, Investigacion clinica.

[45]  K. Davis,et al.  Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. , 2004, The American journal of psychiatry.

[46]  M. Fitzgerald,et al.  Plasma Amino Acid Levels in Children with Autism and Their Families , 2003, Journal of autism and developmental disorders.