GABA dysfunction in schizophrenia: The GABAA receptor as a potential therapeutic target

Abstract

Schizophrenia is a complex psychiatric disorder characterized by debilitating positive, negative, and cognitive symptoms, whose etiology is traditionally attributed to dopamine dysregulation. While dopamine receptor antagonists effectively alleviate positive symptoms, they fail to address the persistent cognitive and negative symptom domains of disease. Growing evidence supports a broader neurobiological framework in which cortical excitation-inhibition (E/I) imbalance acts as an upstream contributor to dopaminergic dysregulation in schizophrenia, with the neurotransmitters gamma-aminobutyric acid (GABA) and glutamate playing a critical role in this homeostasis. Herein, we summarize such evidence, including preclinical findings from animal models of schizophrenia that support the role of GABAergic dysfunction in disease pathophysiology and validate the GABA_A receptor as a promising therapeutic target. We review the potential of subtype-selective GABA_A receptor modulators to restore E/I balance and improve symptoms currently resistant to antidopaminergic agents. Key challenges and considerations for the future development of these therapeutics are also discussed, emphasizing the importance of targeting E/I imbalance to better understand and treat the network-level dysfunction underlying schizophrenia.