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Extrasynaptic GABAA Receptors and Tonic Inhibition in Spinal Cord

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Extrasynaptic GABAA Receptors

Part of the book series: The Receptors ((REC,volume 27))

Abstract

γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult central nervous system (CNS), exerts its physiological effects by acting on ligand-gated chloride-permeable channels termed GABAA receptors (GABAAR). The activation of these receptors produces two different types of inhibition: fast and tonic, mediated by synaptic and extrasynaptic GABAARs, respectively. The molecular conformation of the extrasynaptic GABAA receptors and the tonic inhibitory current they generate have been characterized in different brain structures, and their relevance in controlling neuronal excitability has been also demonstrated. Likewise, a role for these receptors has been suggested in a variety of neurological disorders such as schizophrenia, epilepsy, and Parkinson disease. In the spinal cord, the characterization of these receptors has initiated with the study of their relationship with motor control, chronic pain and anesthesia. This chapter highlights past and present developments in the field of extrasynaptic GABAA receptors and emphasizes their subunit composition, distribution, and physiological role in the spinal cord.

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Authors and Affiliations

  1. Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies of the National Polytechnic Institute (Cinvestav-IPN), Avenida IPN 2508, Col. Zacatenco, 07300, Mexico City, Mexico

    Emanuel Loeza-Alcocer, Carmen Andrés, Justo Aguilar & Rodolfo Delgado-Lezama

  2. Department of Cell Biology, Cinvestav-IPN, Avenida IPN 2508, Col. Zacatenco, 07300, Mexico City, Mexico

    Ricardo Felix

Authors
  1. Emanuel Loeza-Alcocer
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  2. Carmen Andrés
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  3. Justo Aguilar
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  4. Ricardo Felix
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  5. Rodolfo Delgado-Lezama
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Correspondence to Rodolfo Delgado-Lezama .

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Editors and Affiliations

  1. Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom

    Adam C. Errington

  2. Dept. of Physiology & Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

  3. School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Vincenzo Crunelli

Concluding Remarks

Concluding Remarks

Extrasynaptic GABAA receptors containing α4, α6, and α5 subunits represent < 15 % of the total GABAAR population in the CNS. However, they seem to play an important role in controlling neuronal excitability, as well as in motor control, and locomotor function.

In contrast to the extensive research conducted to characterize the expression and function of extrasynaptic GABAARs in supraspinal neurons, much less research attention has been paid to the spinal cord. For example, though most of the extrasynaptic GABAAR subunits have been identified in the spinal cord, little is known concerning their function in pre and postsynaptic membranes. To our knowledge, there is only one report demonstrating the presence of a GABAergic tonic current in spinal cord motoneurons (Castro et al. 2011a) , and also, just a few characterizing the GABAergic tonic current in other cell types including ventral horn interneurons (Grasshoff et al. 2008; Castro et al. 2011b) dorsal horn interneurons (Takahashi et al. 2006; Mitchell et al. 2007; Han and Youn 2008; Bonin et al. 2011) and chick embryo spinal cord neurons (Yang and Zorumski 1989; Chub and O’Donovan 2001) . Therefore, the physiological role of the GABAergic tonic current is far from being elucidated.

Recent studies have shown that spinal motoneuron excitability is modulated by high affinity GABAA receptors tonically active by ambient GABA. Although it is known that shunting its membrane allow neurons to filter out irrelevant inputs responding with an action potential only to pertinent information (Bautista et al. 2010) , additional research is needed to understand which GABAARs mediate the tonic inhibitory current in motoneurons and how they perform such an important task. Likewise, identifying the source of GABA is a relevant topic for future studies.

Interestingly, investigation into the field of pain has been performed to identify the GABAAR isoforms responsible for spinal antihyperalgesia. Using a molecular approach, it has been possible to determine the benzodiazepine-sensitive α subunit involved in spinal in this process. Knabl et al. (2008) found strong spinal antihyperalgesia attenuation in mice harboring a point-mutation in the α2 subunit and less attenuation in mice with a point-mutation in the α3–α5-subunits . In line with this, studies carried out in rodent pain models have shown that by modifying the activity of pre- and postsynaptic GABAARs with allosteric modulators, it is possible to induce antihyperalgesia. However, more research is necessary to confirm the possible participation of extrasynaptic GABAAR activity in neurons and primary afferents involved in nociception (Zeilhofer et al. 2012) . Of particular interest is the modulation of the DRR in primary afferents by extrasynaptic GABAA receptors because they can be blocked without producing the undesirable side effects of classical benzodiazepines such as sedation. Likewise, based on their modulatory effects on spinal reflexes and stereotyped locomotor activity in the spinal cord of different species (adults and neonates), it is reasonable to suggest that in addition to the potential therapeutic roles in anesthesia and nociception, novel GABAAR ligands would provide novel therapeutic tools to improve motor and locomotor activity after spinal cord injury or related pathophysiological conditions (e.g., multiple sclerosis).

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Loeza-Alcocer, E., Andrés, C., Aguilar, J., Felix, R., Delgado-Lezama, R. (2014). Extrasynaptic GABAA Receptors and Tonic Inhibition in Spinal Cord. In: Errington, A., Di Giovanni, G., Crunelli, V. (eds) Extrasynaptic GABAA Receptors. The Receptors, vol 27. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1426-5_8

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