A circuit-based framework is proposed to understand gene and neurotransmitter interactions in schizophrenia. The framework highlights the role of NMDA receptor hypofunction, which reduces the excitation of fast-spiking interneurons, leading to disinhibition of pyramidal cells. This disinhibition can drive a hyperdopaminergic state, contributing to psychosis. GABAergic deficits are also implicated, with reduced GAD67 and parvalbumin in interneurons, leading to decreased GABA synthesis and release. These changes are part of a homeostatic mechanism where NMDA receptors act as sensors for pyramidal cell activity. Disinhibition also reduces gamma oscillations, which may contribute to negative and cognitive symptoms. Nicotine enhances interneuron output, potentially aiding in schizophrenia treatment. The hyperdopaminergic state is linked to hippocampal dysfunction, which may explain some cognitive deficits. The cholinergic system also plays a role in reversing disinhibition and cognitive deficits. Risk genes involved in glutamatergic, nicotinic, and GABAergic systems are discussed, with a focus on their synergistic interactions. The framework integrates findings from multiple neurotransmitter systems and highlights the importance of circuit-level interactions in understanding schizophrenia.A circuit-based framework is proposed to understand gene and neurotransmitter interactions in schizophrenia. The framework highlights the role of NMDA receptor hypofunction, which reduces the excitation of fast-spiking interneurons, leading to disinhibition of pyramidal cells. This disinhibition can drive a hyperdopaminergic state, contributing to psychosis. GABAergic deficits are also implicated, with reduced GAD67 and parvalbumin in interneurons, leading to decreased GABA synthesis and release. These changes are part of a homeostatic mechanism where NMDA receptors act as sensors for pyramidal cell activity. Disinhibition also reduces gamma oscillations, which may contribute to negative and cognitive symptoms. Nicotine enhances interneuron output, potentially aiding in schizophrenia treatment. The hyperdopaminergic state is linked to hippocampal dysfunction, which may explain some cognitive deficits. The cholinergic system also plays a role in reversing disinhibition and cognitive deficits. Risk genes involved in glutamatergic, nicotinic, and GABAergic systems are discussed, with a focus on their synergistic interactions. The framework integrates findings from multiple neurotransmitter systems and highlights the importance of circuit-level interactions in understanding schizophrenia.