Alteration of Plasma Glutamate and Glutamine Levels in Children with High-Functioning Autism
Background
It has recently been hypothesized that hyperglutamatergia in the brain is involved in the pathophysiology of autism. However, there is no conclusive evidence of the validity of this hypothesis. As peripheral glutamate/glutamine levels have been reported to be correlated with those of the central nervous system, the authors examined whether the levels of 25 amino acids, including glutamate and glutamine, in the platelet-poor plasma of drug-naïve, male children with high-functioning autism (HFA) would be altered compared with those of normal controls. Methodology/
Principal Findings
Plasma levels of 25 amino acids in male children (N?=?23) with HFA and normally developed healthy male controls (N?=?22) were determined using high-performance liquid chromatography. Multiple testing was allowed for in the analyses. Compared with the normal control group, the HFA group had higher levels of plasma glutamate and lower levels of plasma glutamine. No significant group difference was found in the remaining 23 amino acids. The effect size (Cohen's d) for glutamate and glutamine was large: 1.13 and 1.36, respectively. Using discriminant analysis with logistic regression, the two values of plasma glutamate and glutamine were shown to well-differentiate the HFA group from the control group; the rate of correct classification was 91%.
Conclusions/Significance The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.
Blood Levels of Glutamate and Glutamine in Recent Onset and Chronic Schizophrenia Caroline Madeira1, Flavio V. Alheira2, Marilia A. Calcia2, Thuany C. S. Silva2, Filippe M. Tannos2, Charles Vargas-Lopes1, Melissa Fisher3,4, Nelson Goldenstein2, Marco Antonio Brasil2, Sophia Vinogradov3,4, Sergio T. Ferreira5,6* and Rogerio Panizzutti1,2* 1Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 2Serviço de Psiquiatria e Psicologia Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 3Department of Psychiatry, School of Medicine, University of California, San Francisco, San Francisco, CA, United States 4Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States 5Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 6Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Converging evidence indicates that dysfunctions in glutamatergic neurotransmission and in the glutamate-glutamine cycle play a role in the pathophysiology of schizophrenia. Here, we investigated glutamate and glutamine levels in the blood of patients with recent onset schizophrenia or chronic schizophrenia compared to healthy controls. Compared with healthy controls, patients with recent onset schizophrenia showed increased glutamine/glutamate ratio, while patients with chronic schizophrenia showed decreased glutamine/glutamate ratio. Results indicate that circulating glutamate and glutamine levels exhibit a dual behavior in schizophrenia, with an increase of glutamine/glutamate ratio at the onset of schizophrenia followed by a decrease with progression of the disorder. Further studies are warranted to elucidate the mechanisms and consequences of changes in circulating glutamate and glutamine in schizophrenia.
Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia
Abstract The neuropsychological effect of hyperammonemia is variable. This study tests the hypothesis that the effect of ammonia on the neuropsychological function in patients with cirrhosis is determined by the ability of the brain to buffer ammonia-induced increase in glutamine within the astrocyte by losing osmolytes like myo-inositol (mI) and not by the magnitude of the induced hyperammonemia. Fourteen cirrhotic patients with no evidence of overt hepatic encephalopathy were given a 75-g amino acid (aa) solution mimicking the hemoglobin molecule to induce hyperammonemia. Measurement of a battery of neuropsychological function tests including immediate memory, ammonia, aa, and short-echo time proton magnetic resonance spectroscopy were performed before and 4 h after administration of the aa solution. Eight patients showed deterioration in the Immediate Memory Test at 4 h. Demographic factors, severity of liver disease, change in plasma ammonia, and aa profiles after the aa solution were similar in those that showed a deterioration compared with those who did not. In patients who showed deterioration in the memory test, the mI-to-creatine ratio (mI/Cr) was significantly lower at baseline than those that did not deteriorate. In contrast, the glutamate/glutamine-to-Cr ratio was significantly greater in the patients that deteriorated. The observation that deterioration in the memory test scores was greater in those with lower mI/Cr supports the hypothesis that the neuropsychological effects of induced hyperammonemia is determined by the capacity of the brain to handle ammonia-induced increase in glutamine.
Overview Summary Prolonged excitation is toxic to nerve cells. Neurobiologists recognize that the nerve cell messenger, glutamate, can cause harm when its messages are overwhelming. Normally glutamate is swiftly cleared from the nerve cell junctions to keep the messages brief. Molecules called transporters aid in keeping glutamate in proper concentrations around nerve cells. Abundant evidence points to glutamate as a destructive factor in ALS and investigators are working to find out how this can be changed. Gene therapy approaches are under investigation to deliver glutamate transporters to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation.
glutamate A diseased neuron. NIH What is Glutamate? Nerve cells pass signals to each other and to their target organs by releasing messenger molecules, called transmitters. Many are simple amino acids such as the one called glutamate. The message is intended to tell the recipient neuron whether to fire off its own neurotransmitters. As with all neurotransmitters, glutamate docks at specific recognition molecules on the receiving neuron. Glutamate is then swiftly cleared from the nerve cell junctions to keep the message brief. Prolonged excitation is toxic to nerve cells, and neurobiologists recognize that glutamate can cause harm when the messages are overwhelming, as in stroke or epilepsy.
Glutamate’s toxicity is apparently due to calcium flooding the cell. Calcium is supposed to briefly enter the neuron with each signal and triggers the cell to fire off its own signals and adjust its own activities accordingly. But prolonged calcium inside the cell evidently can do damage, and will even activate programmed cell death.
