The article presents a circuit-based framework to understand the synergistic interactions between genes and neurotransmitters in the development of schizophrenia. It highlights the role of NMDA receptor hypofunction, which reduces the excitation of fast-spiking interneurons, leading to disinhibition of pyramidal cells and subsequent hyperdopaminergic states. The framework also discusses the impact of NMDA receptor hypofunction on GABAergic interneurons, including reduced expression of GAD67 and parvalbumin, and the resulting compensatory upregulation of postsynaptic GABA receptors. The authors explore how these changes can lead to cognitive deficits and negative symptoms, and how nicotine, a common self-medication among schizophrenic patients, might reverse these effects by enhancing interneuron function. The article emphasizes the importance of integrating genetic and neurotransmitter systems to understand the complex pathophysiology of schizophrenia.The article presents a circuit-based framework to understand the synergistic interactions between genes and neurotransmitters in the development of schizophrenia. It highlights the role of NMDA receptor hypofunction, which reduces the excitation of fast-spiking interneurons, leading to disinhibition of pyramidal cells and subsequent hyperdopaminergic states. The framework also discusses the impact of NMDA receptor hypofunction on GABAergic interneurons, including reduced expression of GAD67 and parvalbumin, and the resulting compensatory upregulation of postsynaptic GABA receptors. The authors explore how these changes can lead to cognitive deficits and negative symptoms, and how nicotine, a common self-medication among schizophrenic patients, might reverse these effects by enhancing interneuron function. The article emphasizes the importance of integrating genetic and neurotransmitter systems to understand the complex pathophysiology of schizophrenia.