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Introduction to Cognition

Question:

Discuss about the Recent Evidence Implicating Subtype Of GABA.

Cognition refers to the action or the mental process that involves acquiring an understanding and knowledge through experience, thought, and the senses. The term often encompasses attention, memory, working memory, evaluation, judgment, decision-making and problem solving (Pessoa et al. 2012). The branch of social psychology also uses cognition to explain different attribution, attitudes and group dynamics. Originally, emotion was not considered a part of cognition. However, recent research evidences have also started encompassing an individual’s awareness of self-strategies and cognitive methods, commonly referred to as metacognition. γ-aminobutyric acid (GABA) is the endogenous ligand and acts as the primary inhibitory neurotransmitter in the CNS. Recent evidences suggest that cognitive decline can be tackled by boosting neuronal excitation with the use of acetylcholinesterase inhibitors (Colovic et al. 2013). This essay will elaborate on the role of GABA(A) receptors, their subtypes and role in cognitive impairment and infection.

The GABA(A) receptors are trans-membrane proteins that comprise of five subunits, which are arranged around the central pore. Functional properties of the receptor are determined by composition of the subunits, along with the AMPA and NMDA receptors. Upon activation, these receptors are found to selectively conduct chloride ions through the central pore, thereby resulting in neuronal hyperpolarisation (Tanaka and Bowery 2012). This results in an immediate inhibitory effect on transmission of neural impulses by diminishing changes of successful action potential. Apart from GABA, other drugs, such as, gaboxadol, muscimol, and bicuculline are found to bind to the active site. Mammals are found to contain a repertoire of several subunits namely, α1–6, β1–3, δ, ε, γ1–3, π, and ρ1–3 (Figure 1). These subunits display distinct expressions in the CNS (Sigel and Steinmann 2012). The cys-loop of transmitter gated ion channels include GABA(A) receptors that has been identified as a major inhibitory receptor target in the mammalian nervous system. Molecular pharmacological studies and rodent gene manipulation studies have revealed GABA(A) receptor’s role in mediating several aspects of anaesthetic behavioural repertoire (Weir, Mitchell and Lambert 2017).

Figure 1- Schematic representation of subunits of GABA(A) receptors

Source- (Sigel and Steinmann 2012)

The receptors also act as essential targets of several benzodiazepines, such as, diazepam and midazolam that enhance the interaction by acting as positive allosteric modulators. Research evidence suggested that more than 500 subtypes of the GABA(A) receptors are found in the human brain. However, owing to the fact that number of abundant receptors are relatively small, majority of the subtypes are found to be composed of three subunits, namely, α, β, and γ. Allosteric agonist compounds are responsible for enhancing action of the GABA(A) receptors. They demonstrate anticonvulsant, anxiolytic and sedative effects.


Post-operative cognitive dysfunction often occurs as a result of cognitive function decline that impairs executive and memory functions. Such cognitive impairment are most commonly exhibited by patients after undergoing surgeries, commonly cardiac surgeries, which involved anaesthesia. It has also been found in major non-cardiac surgeries as well. Furthermore, it is also common among elderly patients who demonstrate an increased likelihood of suffering from its long term impacts. An extensive research on POCD has provided significant evidences that correlate it with GABA(A) receptors. Long-term effects related to such cognitive impairment include loss of memory and a reduction in the ability to concentrate or learn. On the other hand, findings also suggest the the short and long-term effects of juvenile stressor exposure on GABA(A) receptor subunits and establish their correlation with region and age-specific behavioural alterations (Jacobson-Pick and Richter-Levin 2012).

GABA(A) Receptor Structure and Function

Patients who have been hospitalized due to infection most often report IQ levels, lower than the average. Studies have also established the role of GABA receptor’s subunit composition in affecting higher brain functions and neuronal processes (Gassmann and Bettler 2012). The principal mode of action of such infection often encompasses peripheral inflammation of the CNS and the immune system that is associated with neuro-cognitive function. Previous researches have also established a correlation between infection rates and post-operative cognitive decline (Vacas et al. 2013). General anaesthetics have also been found to possess memory blocking properties that increases neuronal inhibition of the GABA(A) receptors. This results in subsequent changes in synaptic plasticity and downregulation of glutamatergic neurotransmission. These findings helped in correlating memory disorders with use of anaesthetics (Wang and Orser 2011).


According to recent evidences, the human brain is complex and is capable of developing specialized mechanisms that help to group principal cells in temporal coalitions that involve distant or local networks. Studies also examined effects of non-amnestic or amnestic cognitive impairment in medication use with GABAergic, antihistamine, anticholinergic, or opioid effects (Tannenbaum et al. 2012). Furthermore, research findings also suggest that cognition deficits that occur due to anaesthesia are manifested in the form of dysregulation of the aforementioned inhibitory interneuron clocking networks. GABA(A) receptors are involved in paralleling the huge diversity of the interneuron. Molecular pharmacology researchers suggest that general anaesthetics, such as, propofol and etomidate exert their action upon the major inhibitory receptors, GABA(A), present in the mammalian CNS. Anti-inflammatory properties of isoflurane and sevoflurane bring about a positive allosteric modulation of the receptors (Gallos and Emala 2013).

Anaesthetic drugs are found to exhibit allosteric modulation on the GABA(A) receptors, thereby disrupting the normal physiological circuits that need a precise timing related to GABA-ergic inputs. Research studies have identified that propofol anaesthetic binds to sites on the receptors that contain β3 homopentamers and α1β3 heteropentamers. These binding sites are located close to anaesthetic sensitivity determinants in the transmembrane domain. Mutagenesis in the beta subunit are found to influence propofol action (Yip et al. 2013).

Effects of propofol and isoflurane-mediated apoptosis in cognitive impairment, triggered by GABA receptor activation have been extensively studied (Yang et al. 2014) (Figure 2). Strong evidences are provided by research studies using a murine model that supported the fact that brain function depression during anesthesia is primarily attributed to γ-aminobutyric acid type A receptor’s increased activity. Upon administration of the anaesthetic etomidate, in-vivo, the cell surface expression and tonic inhibitory current of GABA(A) receptors containing the α subunit was found to increase. This resulted in memory impairment and disruption of hippocampus plasticity. However, the memory deficits were found to be reversed upon inhibition of the receptors (Zurek et al. 2014).

Similar findings were shown by a study that investigated association between memory loss pathogenesis and inflammation. The results suggested that memory deficits could be reversed by inhibiting the alpha subtype of GABA(A) receptors. A pro-inflammatory cytokine interleukin-1β upregulated the tonic inhibitory current in the receptors, and subsequent cell surface expression. This was mediated by the p37 MAPK pathway. Thus, increase in expression of IL-1β impairs memory performance (Wang et al. 2012).

GABA(A) Receptor’s Role in Cognitive Impairment

Figure 2- The functional binding sites of different anesthetic drugs in GABA(A) receptor

Source- (Anesthesia Key 2018)

Specific behavioural effects that are exerted by pharmacologic therapeutics are associated with assembly of the receptor subtypes present in different regions of the brain. Benzodiazepines have been associated with α1 subunits and the α2 subunits have been correlated with anxiolysis in the limbic system (Figure 3). However, there is lack of research evidences that establish evidence for anaesthetic induced neuro-degeneration in surgical conditions (Shu et al. 2012).

Figure 3- Association of benzodiazepine with GABA(A) subunits

Source- (Samardzic and Strac 2016)

Furthermore, evidences also indicate that isoflurane is responsible for selectively enhancing intrasynaptic GABA currents among the α1 –2, β2 –3, and γ2 subtypes. According to research studies, receptors that contain an α subunit, show most sensitivity to volatile general anaesthetic drugs. This is confirmed by co-transfectin experiments that use HEK293 cells with the β1 subunit cDNAs containing either α1 or α2 subtypes. Interactions between GABA(A) receptors and intravenous anaesthetics occur within or near the β subtypes. This can be attributed to less specific subcellular localization shown by the β subtypes, upon comparison with the α subunit (Hines et al. 2012). Thus, intravenous anaesthetics may not always demonstrate distinct physiological differences among extra-synaptic and intra-synaptic GABA(A) receptors, throughout the brain. The necessity of tonic inhibition in regulating consciousness states is highlighted by the action of extrasynaptic GABAA receptors as key targets for sleep-promoting drugs, anaesthetics, alcohol, and neurosteroids (Brickley and Mody 2012).


Protozoan parasite mediated infections use utilise the receptors as the carbon source that supports parasite metabolism and facilitates their dissemination by bringing about stimulation of dendritic-cell motility (Fuks et al. 2012). According to research findings, type II ME49 Toxoplasma mediated infections disrupt glutamic acid decarboxylase 67 (GAD67) enzymes, which play a major role in catalyzing GABA synthesis (Brooks et al. 2015).

Moreover, benzodiazepines are thought to increase vulnerability to infection by mediating the α1 subtypes that are dependent on GABA signalling cascades. GABA receptors have also been identified to play motogenic function and immunomodulation, cell migration, and metastasis. Helicobacter pylori infection has also been related to cognitive impairment, which in turn is mediated by the α1 subtypes of GABA(A) receptors (Budzy?ski and K?opocka 2014).

To conclude, it can be stated that activated immune response, infections and anaesthesia use during surgeries greatly affect several pathways of the brain that is controlled by the GABA(A) receptors. Infectious burden occurs are commonly referred to as measures of exposure to pathogens that are associated with cognitive functioning of the brain. Post-operative delirium also creates significant impacts on cognitive impairment, particularly the geriatric surgical population. Thus, there is a need to conduct more research studies to determine the probable role of receptor subtypes in the higher mental faculties of the brain.

References

Anesthesia Key. (2018). Molecular Mechanisms of Drug Actions: From Receptors to Effectors. [online] Available at: https://aneskey.com/molecular-mechanisms-of-drug-actions-from-receptors-to-effectors/ [Accessed 18 Mar. 2018].

Brickley, S.G. and Mody, I., 2012. Extrasynaptic GABAA receptors: their function in the CNS and implications for disease. Neuron, 73(1), pp.23-34.

GABA(A) Receptor’s Role in Infection

Brooks, J.M., Carrillo, G.L., Su, J., Lindsay, D.S., Fox, M.A. and Blader, I.J., 2015. Toxoplasma gondii infections alter GABAergic synapses and signaling in the central nervous system. MBio, 6(6), pp.e01428-15.

Budzy?ski, J. and K?opocka, M., 2014. Brain-gut axis in the pathogenesis of Helicobacter pylori infection. World Journal of Gastroenterology: WJG, 20(18), p.5212.

Colovic, M.B., Krstic, D.Z., Lazarevic-Pasti, T.D., Bondzic, A.M. and Vasic, V.M., 2013. Acetylcholinesterase inhibitors: pharmacology and toxicology. Current neuropharmacology, 11(3), pp.315-335.

Fuks, J.M., Arrighi, R.B., Weidner, J.M., Mendu, S.K., Jin, Z., Wallin, R.P., Rethi, B., Birnir, B. and Barragan, A., 2012. GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii. PLoS pathogens, 8(12), p.e1003051.

Gallos, G. and Emala, C.W., 2013. Anesthetic Effects on γ-Aminobutyric Acid A ReceptorsNot Just on Your Nerves. Anesthesiology: The Journal of the American Society of Anesthesiologists, 118(5), pp.1013-1015.

Gassmann, M. and Bettler, B., 2012. Regulation of neuronal GABA B receptor functions by subunit composition. Nature Reviews Neuroscience, 13(6), p.380.

Hines, R.M., Davies, P.A., Moss, S.J. and Maguire, J., 2012. Functional regulation of GABA A receptors in nervous system pathologies. Current opinion in neurobiology, 22(3), pp.552-558.

Jacobson-Pick, S. and Richter-Levin, G., 2012. Short-and long-term effects of juvenile stressor exposure on the expression of GABAA receptor subunits in rats. Stress, 15(4), pp.416-424.

Pessoa, L., Padmala, S., Kenzer, A. and Bauer, A., 2012. Interactions between cognition and emotion during response inhibition. Emotion, 12(1), p.192.

Samardzic, J. and Strac, D.S., 2016. Benzodiazepines and Anxiety Disorders: From Laboratory to Clinic. In New Developments in Anxiety Disorders. InTech. Retrieved from- https://www.intechopen.com/books/new-developments-in-anxiety-disorders/benzodiazepines-and-anxiety-disorders-from-laboratory-to-clinic

Shu, Y., Zhou, Z., Wan, Y., Sanders, R.D., Li, M., Pac-Soo, C.K., Maze, M. and Ma, D., 2012. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiology of disease, 45(2), pp.743-750.

Sigel, E. and Steinmann, M.E., 2012. Structure, function, and modulation of GABAA receptors. Journal of Biological Chemistry, 287(48), pp.40224-40231.

Tanaka, C. and Bowery, N.G. eds., 2012. GABA: Receptors, transporters and metabolism. Birkhäuser, pp. 31-44.

Tannenbaum, C., Paquette, A., Hilmer, S., Holroyd-Leduc, J. and Carnahan, R., 2012. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs & aging, 29(8), pp.639-658.

Vacas, S., Degos, V., Feng, X. and Maze, M., 2013. The neuroinflammatory response of postoperative cognitive decline. British medical bulletin, 106(1), pp.161-178.

Wang, D.S. and Orser, B.A., 2011. Inhibition of learning and memory by general anesthetics. Canadian Journal of Anesthesia/Journal canadien d'anesthésie, 58(2), pp.167-177.

Wang, D.S., Zurek, A.A., Lecker, I., Yu, J., Abramian, A.M., Avramescu, S., Davies, P.A., Moss, S.J., Lu, W.Y. and Orser, B.A., 2012. Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors. Cell reports, 2(3), pp.488-496.

Weir, C.J., Mitchell, S.J. and Lambert, J.J., 2017. Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics. British Journal of Anaesthesia, 119, pp.i167-i175.

Yang, B., Liang, G., Khojasteh, S., Wu, Z., Yang, W., Joseph, D. and Wei, H., 2014. Comparison of neurodegeneration and cognitive impairment in neonatal mice exposed to propofol or isoflurane. PloS one, 9(6), p.e99171.

Yip, G.M., Chen, Z.W., Edge, C.J., Smith, E.H., Dickinson, R., Hohenester, E., Townsend, R.R., Fuchs, K., Sieghart, W., Evers, A.S. and Franks, N.P., 2013. A propofol binding site on mammalian GABAA receptors identified by photolabeling. Nature chemical biology, 9(11), pp.715-720.

Zurek, A.A., Yu, J., Wang, D.S., Haffey, S.C., Bridgwater, E.M., Penna, A., Lecker, I., Lei, G., Chang, T., Salter, E.W. and Orser, B.A., 2014. Sustained increase in α5GABA A receptor function impairs memory after anesthesia. The Journal of clinical investigation, 124(12), pp.5437-5441.

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