GABA(A) receptors and their associated proteins: implications in the etiology and treatment of schizophrenia and related disorders

Abstract

Gamma-aminobutyric acid type A (GABA(A)) receptors play an important role in mediating fast synaptic inhibition in the brain. They are ubiquitously expressed in the CNS and also represent a major site of action for clinically relevant drugs. Recent technological advances have greatly clarified the molecular and cellular roles played by distinct GABA(A) receptor subunit classes and isoforms in normal brain function. At the same time, postmortem and genetic studies have linked neuropsychiatric disorders including schizophrenia and bipolar disorder with GABAergic neurotransmission and various specific GABA(A) receptor subunits, while evidence implicating GABA(A)R-associated proteins is beginning to emerge. In this review we discuss the mounting genetic, molecular, and cellular evidence pointing toward a role for GABA(A) receptor heterogeneity in both schizophrenia etiology and therapeutic development. Finally, we speculate on the relationship between schizophrenia-related disorders and selected GABA(A) receptor associated proteins, key regulators of GABA(A) receptor trafficking, targeting, clustering, and anchoring that often carry out these functions in a subtype-specific manner.

Figure 1. The Structure of GABA_A Receptor Subunit

A. The membrane topology of an individual GABA_A receptor subunit, TM1-3 are indicated in blue and TM2 in yellow. B. The tertiary structure of assembled GABA_A receptors. Receptor α subunits are illustrated in blue, β subunits in pink and δ/γ in green. The benzodiazepine binding pocket is formed between α and γ subunits (orange square) and the GABA binding pocket is formed between α and β subunits (pink pentagon).

Figure 2. Summary of modified GABAergic signaling components in psychiatric disease

A. Schematic of relevant GABAergic interneuron synapses onto layer III pyramidal neurons (P) in the dorsolateral prefrontal cortex (DLPFC). Distal dendrites receive GABAergic input from Somatostatin (SST) and neuropeptide Y-expressing Interneurons (NPY) (upper left). The axon initial segment (AIS) is contacted by axons originating from chandelier neurons (Ch) located in layer IV of the DLPFC (lower right). Axons of SST/NPY, P, and Ch neurons are shown in green. B. Hypothetical AIS synapse highlighting some GABAergic synaptic components implicated in schizophrenia and/or bipolar affective disorder. Black arrows indicate reported reductions or elevations in mRNA or protein expression. Red diamonds indicate genetic association with schizophrenia or bipolar disorder.