Sunday, 22 July 2012

GABA Dabba Doo

I'm probably setting myself up for a fall with this quite descriptive post on GABA - gamma aminobutyric acid in relation to autism spectrum conditions given my amateur status in the knowledge stakes regarding the various neurotransmitters. I am however going to chance my luck because more and more frequently GABA seems to be cropping up in the peer-reviewed literature on autism.

Indeed I don't know whether it is just me, but other neurotransmitters such as serotonin (5-HT) seem to be experiencing a slight drop in popularity in autism research circles these days, whilst transmitters like GABA and glutamate, are in the ascendancy. As per every post on this blog (a) no medical advice is intended or given, and (b) always treat my observations with a healthy dose of scepticism.

What is GABA?

Well, I've mentioned glutamate already and indeed glutamate is the core material for making GABA alongside the active form of vitamin B6, pyridoxal phosphate (PLP or P5P) used as a cofactor. The enzyme glutamate decarboxylase (GAD) is essential for this transformation from excitatory neurotransmitter (glutamate) to inhibtory neurotransmitter (GABA). Brain synthesis is an important part of GABA given that it finds some difficulty crossing the blood-brain barrier. Keep in mind both PLP and GAD for later on in this post.

What does it do?

Well, it's a neurotransmitter with corresponding GABA receptors dotted around the central nervous system including in the region of the 'second brain' that is the gastrointestinal tract (here) similar to other neurotransmitters (here). GABA is also described as an inhibitory neurotransmitter (here) similar to glycine; a sort of yin and yang to the excitatory neurotransmitters which modulate the firing of neurons; GABA (generally) decreasing their likelihood of firing.

Over-zealous neuronal firing caused by an 'imbalance' between excitatory and inhibitory neurotransmitters is thought to be involved in conditions like epilepsy (here) and the reason why certain compounds that increase GABA levels in the brain also possess anticonvulsant properties (here). There is also some speculation linking the use of a ketogenic diet and increases in brain GABA synthesis to account for the anticonvulsant observations noted (here) for example. Should I mention that GABA might also possess some anti-inflammatory action (here) too?

So a quick recap: glutamate, GAD and PLP in the brain (and other places) make GABA, an inhibitory neurotransmitter which dampens down neuronal firing and potentially the reason why some antiepileptics (and other compounds) which enhance GABA production/action work the way they do.

Let the cherry-picking begin: GABA and autism.

Where to start...mmm. GABA has been looked at from several perspectives in cases of autism falling into some general categories to include: (a) issues with the receptors for GABA in the brain, and (b) issues with GAD involved with the synthesis of GABA from glutamate. There are other areas (such as autoantibodies to GABAergic neurons)  but the lion's share of research seems to fall into one of these two categories.

(a) GABA receptors are basically the bedfellows of GABA. Several types of GABA receptor are currently known about and have been examined with autism in mind.

  • Quite a bit of research has been done in this area so I am indeed cherry-picking. The comorbidity of autism and epilepsy is obviously a point of real interest given the function of GABA and its receptors as described in this paper by Kang & Barnes*.
  • Various authors have reported on issues with GABA receptors in cases of autism; in the majority suggesting reduced receptor numbers in various parts of the brain (see here, here and here).
  • The genetics of GABA receptors have also been the topic of some research although not wholly convincing in providing an effect (see here and here). I don't want to seem unduly biased against any genetic link to GABA receptors and autism so will balance that last sentence by noting the evidence on for example, gene-gene interactions and GABA receptor genes in autism (see this paper by Ma and colleagues** full-text).

(b) GAD has been mentioned in passing previously on this blog in relation to the imbalance seemingly present between glutamate/glutamine in cases of autism. I can see why this is such an attractive area of study with autism in mind, covering not only the possibility of issues with the formation of GABA but also potentially (and partially) accounting for the 'build up' of glutamate thereby unsettling that delicate excitatory/inhibitory balance. That's my take on it anyway. The body of research published so far suggests:

  • GAD production (the isoforms GAD65 and GAD67) might not be optimal in cases of autism. Yip and colleagues*** noted reduced mRNA levels of GAD67 in Purkinje cells of a group with autism (Purkinje cells being a target for previous autism research based on the suggested involvement of cerebellar function). The same group also reported reduced mRNA levels of GAD65**** (here full-text).
  • Overall, genomic studies which have included the examination of genes thought to be involved in the production of GAD have not yielded any wider significant issues in cases of autism as per the studies by Rabionet and colleagues***** and Buttenschøn and colleagues******.
  • Environment has however been proposed as a possible interfering variable affecting GAD production and function as per the suggestion by Nouel and colleagues******* on the prenatal effects of a bacterial endotoxin on GAD67 (in rats). That and the possibility of autoantibodies to GAD65 being found in a small sub-group of children with autism and ADHD as reported by Rout and colleagues******** (similar antibody findings also being reported in the very interestingly named 'Stiff-Person syndrome', a condition characterised by amongst other things heightened sensitivity to stimuli).

I think you can see that for some people on the autism spectrum, GABA, it's receptors and findings around its manufacture - seems to have a few potential issues attached. Stepping back to the PLP / vitamin B6 link with GABA, there is also some interesting evidence emerging there also with autism in mind. Indeed another familiar name, Jim Adams (he of the vitamin RCT among other things) published a paper********* a few years back indicating high levels of plasma vitamin B6 to be present in cases of autism. You're probably thinking to yourself, well high levels of vitamin B6 is good? Er, not exactly, because high levels of vitamin B6 in unsupplemented individuals as this group were, might actually suggest that vitamin B6 is not being optimally metabolised by pyridoxal kinase into PLP for example. I could start to talk about pyridoxal kinase and ATP complexed to zinc (see here) but then we start asking questions about zinc availability and the whole thing gets really, really complicated.

I think I'll stop there for now with the hope that I have done more informing rather than misinforming. To end, a link to something completely different... The Killers and Mr Brightside.

GABA, Dabba, Doo!


* Kang JQ. & Barnes G. A Common Susceptibility Factor of Both Autism and Epilepsy: Functional Deficiency of GABA(A) Receptors. JADD. May 2012.

** Ma DQ. et al. Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. American Journal of Human Genetics. 2005; 77: 377-388.

*** Yip J. et al. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathologica. 2007; 113: 559-568.

**** Yip J. et al. Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Research. 2009; 2: 50-59.

***** Rabionet R. et al. Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes. Neuroscience Letters. 2004; 372: 209-214.

****** Buttenschøn HN. et al. A population-based association study of glutamate decarboxylase 1 as a candidate gene for autism. The Journal of Neurotransmission. 2009; 116: 381-388.

******* Nouel D. et al. Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring. European Neuropsychopharmacology. 2012; 22: 300-307.

******** Rout UK. et al. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. European Child & Adolescent Psychiatry. 2012; 21: 141-147.

********* Adams JB. et al. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. Journal of Alternative & Complementary Medicine. 2006; 12: 59-63.