The Significance of GABA and G Protein-Coupled Receptors in the Central Nervous System

GABA receptors and G protein-coupled receptors for γ-aminobutyric acid, are both inhibitory neurotransmitters that play significant roles in maintaining various neural pathways in the Central Nervous System, or CNS. Three members of the KCTD family, a potassium (K+) channel tetramerization domain, are primarily responsible for associating with GABAB2. These subunits are KCTD12, -12b, and 16 and they were identified as GABAB receptor subunits, influencing many biochemical properties by their receptor response. GABAB receptors often show decreased expression in many neurological and psychiatric disorders and have thus been the target for treating these neuropsychiatric disorders (Cathormas et al. 2015). In the four experiments discussed, the role of KCTD subunits in GABAB receptors were tested in mice, with the intent of studying a number of the aspects of the gene and extrapolating the results for humans. Overall, the KCTD gene’s location and functionality in a GABAB receptor play a crucial role in maintaining healthy and functioning physiological and psychological processes within the body.

The location within the body of the KCTD 8, 12, and 16 subunits was a key point of interest for the experiments conducted in the four papers. Analysis of the data from a Northern blot test of adult mice tissue, suggests that the KCTD 8, 12, and 16 subunits were expressed primarily in the brain (Metz et al. 2011). Low levels of expression of the KCTD gene were also evident in the intestine, heart, and bone marrow. Different strains of the KCTD16 subunit were also expressed in the spinal cord (Metz et al. 2011). In another experiment, researchers were able to find where KCTD subunits were most concentrated in the brain. Results suggested that KCTD12 was most heavily expressed in the hippocampus and amygdala (Cathormas et al. 2015). KCTD12 is also responsible for stabilizing GABAB receptors on the cell surface. Research of the KCTD12 gene in the amygdala suggest that common neuropsychiatric disorders, such as bipolar disorder, can be associated with a polymorphism in the promoter region of KCTD12 (Ivankova et al. 2013). In fact, as seen in three of the experiments, mice with mutated KCTD12 genes repeatedly presented different emotional and homeostatic behaviors as opposed to mice without the mutated KCTD12 gene. The experiments further explain that the location of the KCTD12 gene has a significant role in understanding the effects of mutated KCTD genes.

The overall function of a normal and healthy KCTD gene is to regulate emotions and memory within the brain. It’s function is responsible for desensitization of the receptor response (Sedik et al. 2012). Desensitization of a gene means that over time the subject being tested will “get used to” the effect of the gene, therefore becoming desensitized to the effect. Since the KCTD gene is primarily located in the hippocampal region of the brain, emotional and cognitive processes require the healthy functioning KCTD gene to be present.. Because of this, a normally functioning gene should produce emotions and responses that are expected, such as a normal response time to given stimuli. Many mice who have a mutated version of the gene do not exhibit signs of recognition and often become desensitized to memory tests. Mice with a mutated gene, “exhibited increased fear learning but not increased memory of a discrete auditory-conditioned stimulus” (Cathomas et al 2015).

Mutations in the KCTD gene have often been associated with many neurological and psychological disorders (Ivankova et al. 2013). Mutation in the GABAB receptors overall has often led to many psychiatric and neurological conditions, including but not limited to epilepsy, anxiety, schizophrenia, and addiction (Ivankova et al. 2013). Researchers also found that by mutating the KCTD12 gene in the brain of mice, their circadian rhythms were altered, in addition to changes in their neuron behaviour and various hormone concentrations. Upon performing electrophysiological recordings on the slices of the hippocampus, in both wild type and KCTD12 mutated mice, researchers also found an increased state of excitability of pyramidal neurons. These neurons are found in the prefrontal cortex of the brain, and play a crucial role in motor development and many cognitive processes (Cathormas et al. 2015). Mice with mutations of KCTD12 gene and KCTD16 gene also displayed much lower response behaviours to reward stimuli, in addition to increased behaviour of reclusiveness and agitation, as opposed to wild type mice. Overall, the KCTD12 and KCTD16 gene play an important role in necessary behaviour and cognitive processes.

The KCTD genes are imperative for healthy physical and cognitive functioning, due to the gene’s important location and its overall responsibilities. The genes regulate behavioral responses and ensure a healthy mindset, which is why many mental and behavioral disorders may occur if there is a mutation in either the KCTD gene or GABAB receptor as a whole. While research has shown that many neuropsychological disorders arise from a dysfunctional KCTD gene, further research is needed in order to determine the specific parts of gene that are mutated. Upon further testing, scientists and medical professionals will be able to better treat those suffering from psychological disorders, by knowing how to successfully target the KCTD gene.