Glutamate Watching

The amino acid glutamate—and its receptor and signalling functions— is fast becoming the one to watch with autism spectrum disorders in mind.

Amino acids and autism

When talking about the possible underlying biochemistry of the heterogeneity of autism, certain key themes seem ever present in the research literature. Amino acids, the basic building blocks of functional chemistry and proteins, by my reckoning rank as some of the most popular compounds of interest from a few perspectives.

Before I start going into the heavy science, a few things are worth knowing. My mentor always provided quite a nice way of thinking about amino acids based on letters, words and sentences. The story goes something like this: proteins are made up of long, long chains of amino acids all stuck together. In effect, proteins are the sentences of biochemistry. Along the way, some proteins as in the example of food derived proteins such as gluten and casein, eventually get broken down into smaller chains of amino acids called peptides. Peptides can be seen as the words of that protein sentence. Peptides again can be broken down into their individual amino acids. Amino acids, the basic unit of the peptide and protein are the individual letters of that biochemical sentence. It is these amino acid building blocks which might offer some tantalizing clues about conditions like autism.

With autism in mind, the chemistry of amino acids is providing some interesting leads. The recent publication of issues with the branched chain amino acids as representing one type of autism is a good example [1]. Indeed, other inborn errors of metabolism such as phenylketonuria (PKU) and the involvement of the amino acid phenylalanine have similarly shown a relationship with the presentation of some cases of autism [2]. Amino acids are also involved in the synthesis of other potentially pertinent compounds linked to autism including carnitine [3], glutathione [4] and indeed the puzzle that is serotonin (derived from the amino acid tryptophan) and autism [5]. One amino acid in particular however seems to be pulling ahead of the pack with autism in mind: glutamate (also known as glutamic acid).

Attention turns to glutamate

Most people will probably have heard mention of glutamate when talking about the food industry and use of the flavour enhancer, monosodium glutamate (MSG). Outside of this link, glutamate also acts as a neurotransmitter, similar to compounds like serotonin and dopamine.

Neurotransmitters serve many important functions and can normally be classified as being either inhibitory or excitatory depending on whether they increase or decrease the likelihood of a neuron firing. Glutamate is an excitatory neurotransmitter in that it generally increases the likelihood of neurons firing. Such a characteristic is probably why glutamate and its transporters show a connection with conditions like epilepsy, where seizure activity may reflect the over-zealous firing of neurons [6]. Indeed with the correlation between autism and epilepsy (seizures estimated to be present in between 5-40% of the autistic population at some point during the lifetime), one can already see how glutamate and its functions may well be implicated in some cases and a potential topic of interest.

With autism in mind, a few findings confirm the possible involvement of glutamate.

Glutamate and glutamine

Plasma and brain levels of glutamate and its amino acid sibling, glutamine, have been the source of some speculation. Abu Shmais and colleagues [7] reported a raised serum glutamate:glutamine ratio in their cohort of boys diagnosed with autism, similar to other findings. The concentration of this ratio in various brain regions [8] was also found to show significant differences in cases of autism. (Note: the amino acid glutamine is a whole other ballgame when it comes to autism.)

Glutamate and GABA

Despite its excitatory link, glutamate is an essential component in the formation of the neurotransmitter GABA (γ-Aminobutyric acid), an inhibitory neurotransmitter. The process of converting glutamate to GABA is reliant on the functioning of glutamate decarboxylase (GAD), an enzyme which itself uses the active form of vitamin B6, PLP (Pyridoxal-phosphate) or P5P, as a cofactor. Outside of some preliminary study of PLP in cases of autism [9], there is some emerging evidence to suggest that both the production of GAD [10] and the functioning of GAD [11] may be perturbed in some cases of autism. Alongside identified issues with GABA receptors, one has to assume that a “blockage” in the conversion of glutamate to GABA may contribute to greater amounts of glutamate being more readily available throughout the body.

Receptors, mice and Fragile X syndrome

Glutamate receptor and signalling functions have also been the topic of some interest regarding autism, or at least conditions associated with autistic symptoms presenting. Metabotropic glutamate receptors, and in particular mGluR5, have been the target of interest related to the presence of Fragile X syndrome (FXS) [12].

Silverman and colleagues [13] for example, reported initial results based on an experimental compound, GRN-529, a glutamate inhibiting compound, based on studies of a mouse model of autism. They found some positive changes to mouse behaviours following compound administration.

More recently, Berry-Kravis and colleagues [14] reported on the administration of arbaclofen to human participants with FXS (identified as carrying the FMR1 gene mutation). They reported some significant effects on participants’ behaviour based particularly in areas of social interaction following administration of the drug. Arbaclofen, a derivative of baclofen, is also known to affect GABA receptors (an agonistic effect) and in turn inhibit the release of glutamate.

Finally, Jung and colleagues [15] again with FXS in mind, described the effects of the Fragile X Mental Retardation Protein (FMRP) loss noted in cases of FXS, on mGluR5 receptor depression and subsequent release of an endocannabinoid, 2-AG (2-arachidonoyl-sn-glycerol). In a mouse model, they described how ‘rescuing’ levels of 2-AG seemed to have some positive impact on mouse observed behaviours, which again may have implications for autism presentation in cases of FXS.

Conclusions

Many of the investigations highlighted in this post on a possible relationship between glutamate and autism spectrum disorders are preliminary. Still further, many studies have relied on the presentation of autistic behaviours in known genetic conditions such as FXS and looked only at mouse models of these conditions to determine any effect, so questioning applicability to more idiopathic cases of autism.  That being said, research on amino acid chemistry with a specific focus on glutamate is beginning to ask some interesting questions relevant to autism which not only cover areas of neurotransmitters and brain function, but likely also other areas of functioning. Importantly also, the prospect of therapeutic interventions to moderate glutamate chemistry and functioning has been suggested that could very well impact on the presentation of behaviours associated with autism and other disorders.

 

References

[1] Novarino G. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. September 2012.

[2] Baieli S. Autism and phenylketonuria. J Autism Dev Disord. 2003; 33: 201-204.

[3] Rossignol DA. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012; 17: 290-314.

[4] Main PA. The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr Metab (Lond). 2012; 9: 35.

[5] Cook EH. Autism: review of neurochemical investigation. Synpase. 1990; 6: 292-308.

[6] Sun DA. Glutamate injury-induced epileptogenesis in hippocampal neurons: an in vitro model of stroke-induced “epilepsy”. Stroke. 2001; 32: 2344-2350.

[7] Abu Shmais GA. Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism.  J Neurodev Disord. 2012; 4: 4.

[8] Page LA. In Vivo 1H-Magnetic Resonance Spectroscopy Study of Amygdala-Hippocampal and Parietal Regions in Autism. Am J Psychiatry 2006; 163: 2189-2192.

[9] Adams JB. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. J Altern Complement Med. 2006; 12: 59-63.

[10] Yip J. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol. 2007; 113: 559-568.

[11] Rout UK. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatry. 2012; 21: 141-147.

[12] Williams SCP. Drugs targeting mGluR5 receptor offer ‘fragile’ hope for autism. Nat Med. 2012; 18: 840.

[13] Silverman JL. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med. 2012; 4: 131ra51.

[14] Berry-Kravis EM. Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med. 2012; 4: 152ra127.

[15] Jung KM. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun. 2012; 3: 1080.

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