Targeting Cognitive Deficits in Schizophrenia via GABAA Receptors: Focus on α2, α3, and α5 Receptor Subtypes

Deficits in inhibitory GABAergic neurotransmission are likely involved in the pathophysiology of schizophrenia, specifically in cognitive deficits, positive symptoms, and possibly also negative symptoms. GABA_A receptors are heteropentamers that are typically classified based on their subunits. Different GABA_A receptors have been shown to have distinct physiological and pharmacological functions, and animal models suggest that dysfunction in neuronal circuits containing alpha2-GABA_A and possibly α5-GABA_A receptors contributes to cognitive deficits and that dysfunction in neuronal circuits containing α3-GABA_A or α5-GABA_A receptors contribute to increased dopaminergic activity. The α2/α3-selective positive allosteric modulator TPA023 (MK-0777) reduced ketamine-induced memory deficit in primates, and the α5-selective positive allosteric modulator SH-053-2F-R-CH₃ reduced hyperactivity of the dopamine system in the rat methylazoxymethanol acetate (MAM) developmental model of schizophrenia. Thus, despite a negative phase II study with TPA023 (MK-0777) in humans, more efficacious subtype-selective GABA_A receptor modulators may become useful therapeutic agents targeting cognition and specific pathophysiological deficits in schizophrenia.