GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism

Abstract

The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.

Figure 1

Cognition in psychiatric disorders. A global view of cognition and its disruption in psychiatric disorders. Psychiatric disorders are associated with complex and disease-specific patterns of cognitive impairment. Abbreviations: ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum disorders; LTD, long-term depression; LTP, long-term potentiation; OCD, obsessive-compulsive disorder; GAD, generalized anxiety disorder; PTSD, posttraumatic stress disorder. Reprinted from Reference with permission from Macmillan Publishers Ltd.

Figure 2

Distribution of α₅ subunit-containing GABA_A receptors. (a)False colour immunohistochemical distribution of the α₅ GABA_A receptor in parasagittal sections of adult mice; the enlargement of the hippocampal formation immunohistochemical staining shows the prominent dendritic localization of the α₅ subunit (reprinted from Reference , Copyright (2002): National Academy of Sciences, USA). (b) Schematic distribution of GABA_A receptor subtypes at pyramidal cell dendrites (beige). Phasic inhibition is mediated via synaptic α₂ and α₃-subunit-containing GABA_A receptors, whereas α₅ subunit-containing receptors, located at the bases of dendritic spines and the adjacent dendritic shaft, provide tonic inhibition. Abbreviations: GABA, γ-aminobutyric acid; NMDA-R, N-methyl-D-aspartate receptor.

Figure 3

General organization of amygdala circuitry and GABAergic neurons. (a) Scheme of the basic organization and overall flow of information within the amygdaloid complex. (b) Coronal brain slice stained for the 67-kDa isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67); the distribution of GABAergic neurons across the amygdaloid complex is illustrated. (c) Simplified scheme of the organization and function of inhibitory interneurons in amygdaloid nuclei. In the LA and BA, local interneurons are part of feed-forward and feedback circuits, and they control projection neuron output. The lITCs and mITCs relay feed-forward inhibition, which may also participate in controlling CEl output. Abbreviations: BA, basal amygdala; CEl, lateral subdivision of the central amygdala; CEm, medial subdivision of the central amygdala; GABA, γ-aminobutyric acid; LA, lateral amygdala; lITC, lateral intercalated cell cluster; mITC, medial intercalated cell cluster. Reproduced from Reference with permission.

Figure 4

Inhibitory gating of long-term potentiation (LTP) in the lateral amygdala (LA) in fear acquisition and GABA_A receptor distribution. (a) Pyramidal projection neurons in the LA (gray) receive converging thalamic and cortical sensory afferents. LTP at thalamic and cortical sensory synapses, induced by fear conditioning, is tightly controlled by GABA released from feed-forward interneurons (IN) (green). At thalamic afferents, this control is predominantly postsynaptic via GABA_A receptors. At cortical afferents, this control is presynaptic via GABA_B receptors. The GABA IN are targets of neuromodulators that modify their output activity and thereby gate the induction of LTP by transiently altering the levels of pre- and postsynaptic inhibitory drive. By depressing GABA feed-forward inhibition, dopamine and noradrenaline enhance LTP, whereas 5-hydroxytryptamine (5-HT) reduces LTP. Reproduced from Reference with permission. (b) Immunohistochemical distribution of GABA_A receptor subtypes in the amygdala. In the mouse, the α₂-subunit staining is prominent throughout, in particular in the central nucleus where no α₁ subunit immunoreactivity is detectable. Both α₁ and α₂ subunits produce a diffuse labeling of neuropil in the lateral and basolateral nuclei. The α₃ subunit is detected in the basolateral nucleus and, to a lesser extent, in the lateral and central nuclei (, ). Similarly, in human amygdala, α₂-subunit staining is prominent throughout and most prevalent in the central and basal nuclei. α₁-Subunit staining was prominent only in the lateral nucleus. Minimal staining for α₃ subunits was apparent throughout the amygdala. Other Abbreviations: AMPA, 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate. Data and image of human amygdala courtesy of J. Song and H. Waldvogel, Center of Brain Research, University of Auckland, New Zealand.