A very basic model of the Insular Cortex was developed in previous posts (see Appendix). In the open model of the Insular Cortex detailed above there is a key role for GABA receptors in determining the intensity of emotional experience. The model is a little simple at the moment and we are at a point where we can begin to add detail. A useful starting point is to take a closer look at the GABA receptor in order to reconcile the neurobiology with the assumptions in the model.
There are two types of GABA receptor – the GABAa and the GABAb receptor. The GABA receptor is found in the Nematode worm which also goes by the name Caenorhabditis elegans (using binomial nomenclature) or C.elegans for short. A video of C.elegans is shown below.
There are two reasons that we might want to briefly look at C.elegans in order to get a better understanding of GABA receptors.
1. C.elegans has been very well studied.
2. C.elegans is a very simple organism and researchers have a more comprehensive (although not exhaustive) understanding of the physiology of C.elegans in contrast with more complex organisms.
Reflecting point 1 above, there is an online resource which I will reference in this post – the Wormbook – an online review of C.elegans biology. This book has a creative commons license and the quotes below are from the section on GABA.
‘γ-aminobutyric acid (GABA) is an amino acid neurotransmitter synthesized by decarboxylation of glutamate by the enzyme glutamic acid decarboxylase. GABA had been long known to exist in plants and bacteria, where it serves a metabolic role in the Krebs cycle‘
Historically GABA was studied in many species and at first it was thought to be a metabolite. There were a few twists and turns in the story before GABA was convincingly established as a neurotransmitter and this is covered in Jogensen’s section of the Wormbook. In C.elegans, GABA has been found to play a role in gut function, locomotion and foraging. C.elegans has a very simple nervous system with only 26 GABA neurons.
‘These 26 GABA neurons are comprised of 6 DD, 13 VD, 4 RME, RIS, AVL and DVB (Figure 2B). These neurons fall into different classes based on their synaptic outputs: the D-type neurons, that is, the 6 DD and 13 VD motor neurons, innervate the dorsal and ventral body muscles, respectively; the 4 RME motor neurons innervate the head muscles; the AVL and DVB motor neurons innervate the enteric muscles; and RIS is an interneuron (White et al., 1986)‘
In the video of C.elegans above you can see the worms wriggling as they move across the screen. They are able to achieve this movement by relaxing some of their muscles using GABA. The unopposed muscle then steers the movement. What is fascinating about this are the many parallels with GABA function in humans. However although there are parallels with GABA receptors and GABA function in vertebrates we must remember that all species continue to adapt. Therefore even though vertebrates and C.elegans shared a common ancestor at one point, further ahead in time the function of the same gene may be lost or find an altogether different use in either lineage. Jogensen comments that
‘Nematodes and vertebrates diverged over 800 million years ago. Nevertheless the proteins governing GABA cell identity, biosynthesis and transport are conserved in the nematode and vertebrate nervous systems. Notably, studies in the nematode identified the vesicular GABA transporter and the UNC-30 homeodomain transcription factor, and subsequent genome comparisons identified the vertebrate orthologs of these genes. Although there does not appear to be a GABA-gated cation channel related to EXP-1 in the vertebrate genome, the GABAA channel and the GABAB chloride G-protein coupled receptor are both found in the vertebrate and nematode genomes‘
There are a few genes which are known to be related directly to GABA and mutations in these genes are described in the table below. There are also a few GABA related function but which are yet to be matched with genes.
Jorgensen clarifies the role of some of these gene/gene functions in C.elegans.
‘In summary, UNC-30 is required for GABA neuron specification in the D-type neurons and its expression is sufficient for conferring GABA neuron identity. However, its role in cell identity is complicated. UNC-30 is not required by all GABA neurons for GABA cell identity. How these cells regulate neurotransmitter specificity is not known. Moreover, some cells that express UNC-30 do not display GABA cell identity. Why these cells do not express GABA specific genes is not known‘
‘GABAA receptors are GABA-gated chloride channels that inhibit cell activity. The GABAA receptor, that inhibits body muscle contraction during locomotion, is encoded by the unc-49 gene (Figure 6; Bamber et al., 1999; Bamber et al., 2005). The unc-49 locus encodes three distinct GABA receptor subunits by splicing a common N-terminal ligand-binding domain to one of three alternative C-terminal domains, producing the UNC-49A, UNC-49B, and UNC-49C subunits (Bamber et al., 1999). Keep in mind that these alternative gene products are all subunits of a GABAA ligand-gated ion channel and are not related to GABAB receptors. This unusual gene structure is conserved in the distantly-related nematode C. briggsae. The UNC-49B and UNC-49C subunits are expressed in the muscles and localized to synapses from the D-type GABA motor neurons (Bamber et al., 1999; Bamber et al., 2005; Gally and Bessereau, 2003). The GABA receptor at neuromuscular junctions is a heteromer composed of the B and C subunits (Bamber et al., 2005). The B subunit is required for localization of the receptor to neuromuscular junctions and the C subunit imparts specific pharmacological properties to the heteromeric receptor (Bamber et al., 2005; Bamber et al., 2003). The UNC-49A subunit is barely detectable in vivo, and does not heteromultimerize with UNC-49B or UNC-49C to form a functional receptor in vitro (Bamber et al., 1999)‘.
From the above, we therefore know that there are a number of genes involved in GABA related functions in C.elegans and that the physiological function has been well characterised but there are still pieces of the jigsaw missing. There are some useful points here but in terms of the model we will need to take a closer look at GABA and GABA receptors in humans.
Jorgensen, E.M. GABA (August 31, 2005), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.14.1, http://www. wormbook.org.
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