Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors

Tija C Jacob

doi:10.3389/fnmol.2019.00179

Abstract

α5 subunit containing GABA type A receptors (GABAARs) have long been an enigmatic receptor subtype of interest due to their specific brain distribution, unusual surface localization and key role in synaptic plasticity, cognition and memory. These receptors are uniquely positioned to sculpt both the developing and mature hippocampal circuitry due to high overall expression and a distinct peak within the critical synapse formation period during the second postnatal week. Unlike the majority of other GABAARs, they exhibit both receptor clustering at extrasynaptic sites via interactions with the radixin scaffold as well as synaptic sites via gephyrin, thus contributing respectively to tonic currents and synaptic GABAergic neurotransmission. α5 GABAAR signaling can be altered in neurodevelopmental disorders including autism and mental retardation and by inflammation in CNS injury and disease. Due to the unique physiology and pharmacology of α5 GABAARs, drugs targeting these receptors are being developed and tested as treatments for neurodevelopmental disorders, depression, schizophrenia, and mild cognitive impairment. This review article focuses on advances in understanding how the α5 subunit contributes to GABAAR neurobiology. In particular, I discuss both recent insights and remaining knowledge gaps for the functional role of these receptors, pathologies associated with α5 GABAAR dysfunction, and the effects and potential therapeutic uses of α5 receptor subtype targeted drugs.

Highlights

Structure, Distribution and CompositionGABA type A receptors (GABAARs) are heteropentameric ligand-gated chloride (Cl−) ion channels typically composed of two α (α1–6), two β (β1–3), and one γ (γ1–3) or δ subunit (Figure 1A)
The two αβ NT interfaces form GABA binding sites composed of the α5-GABAA Receptors and Therapeutic Potential principal (+) side of the β subunit and the complementary α subunit (−) side, while a single α+(1, 2, 3 or 5)/γ2interface generates the primary binding site for benzodiazepines, which are allosteric positive modulators of the GABAAR and an important clinical sedative-hypnotic-anxiolytic drug class
Over a third of the neurons in the internal granule cell layer have α5 GABAARs (Sur et al, 1999), the function here is unknown. α5 GABAARs are expressed in the spinal cord, where they contribute to presynaptic inhibitory control over sensory-motor transmission (Lucas-Osma et al, 2018) and are implicated in resolution of hyperalgesia (Perez-Sanchez et al, 2017)

Summary

INTRODUCTION

GABA type A receptors (GABAARs) are heteropentameric ligand-gated chloride (Cl−) ion channels typically composed of two α (α1–6), two β (β1–3), and one γ (γ1–3) or δ subunit (Figure 1A). While α5 containing GABAARs makeup only approximately 5% of the total receptor population in the brain, they are highly expressed in both the hippocampus and olfactory bulb. They represent close to 25% of all hippocampal GABAAR (Olsen and Sieghart, 2009) and are abundant in CA1 and CA3. Our recent mass spectrometry analysis identified a specific increase in α5βγ containing receptors in the cortex following diazepam injection, consistent with benzodiazepine exposure leading to modification of GABAAR composition and potentially drug effects through α5 plasticity (Lorenz-Guertin et al, 2019)

Subcellular Localization

Therapeutic potential

Findings

CONCLUSION