Schizophrenia is a complex disorder with a heterogeneous presentation, characterized by disorganized, positive, and negative symptoms. Recent research suggests that dysconnectivity, or abnormal functional integration of brain processes, plays a central role in the pathophysiology of schizophrenia. This hypothesis posits that the core pathology in schizophrenia is aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. This neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia. The dysconnection hypothesis also provides a basis for future diagnostic classifications with physiologically defined patient subgroups. The dysconnection hypothesis is supported by evidence from neurophysiology, neuropharmacology, neuropathology, and genetics. Neurophysiological studies show that patients with schizophrenia exhibit reduced mismatch negativity (MMN), a prediction error signal dependent on synaptic plasticity. Neuropharmacological studies indicate that drugs affecting synaptic plasticity can induce psychotic symptoms in healthy subjects, similar to those seen in schizophrenia. Neuropathological findings reveal structural deficits in cortical neurons, potentially linked to impaired synaptic plasticity. Genetic studies highlight the role of genes involved in NMDAR-dependent signaling and plasticity in schizophrenia. The dysconnection hypothesis also explains the interaction between different neurotransmitter systems, particularly the role of NMDAR-dependent plasticity in regulating DAergic and GABAergic functions. This interaction is crucial for understanding the pathophysiology of schizophrenia, including the dysregulation of prefrontal and striatal DAergic activity. The hypothesis further suggests that first-rank symptoms, such as delusions of control and hallucinations, may result from a failure of self-monitoring or corollary discharge mechanisms. These mechanisms are essential for distinguishing between self-generated and externally generated sensory inputs. Impairments in these mechanisms can lead to misattribution of inner speech to external sources, resulting in auditory hallucinations. The dysconnection hypothesis also addresses the clinical heterogeneity of schizophrenia, explaining how different symptoms may arise from variations in the expression of dysfunctional experience-dependent plasticity in the brain. Additionally, it accounts for the sex differences in onset and prevalence, which may be influenced by hormonal factors such as estrogens and androgens. Overall, the dysconnection hypothesis provides a comprehensive framework for understanding the pathophysiology of schizophrenia, linking abnormal synaptic plasticity to a wide range of clinical symptoms and offering a basis for future research and diagnostic approaches.Schizophrenia is a complex disorder with a heterogeneous presentation, characterized by disorganized, positive, and negative symptoms. Recent research suggests that dysconnectivity, or abnormal functional integration of brain processes, plays a central role in the pathophysiology of schizophrenia. This hypothesis posits that the core pathology in schizophrenia is aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. This neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia. The dysconnection hypothesis also provides a basis for future diagnostic classifications with physiologically defined patient subgroups. The dysconnection hypothesis is supported by evidence from neurophysiology, neuropharmacology, neuropathology, and genetics. Neurophysiological studies show that patients with schizophrenia exhibit reduced mismatch negativity (MMN), a prediction error signal dependent on synaptic plasticity. Neuropharmacological studies indicate that drugs affecting synaptic plasticity can induce psychotic symptoms in healthy subjects, similar to those seen in schizophrenia. Neuropathological findings reveal structural deficits in cortical neurons, potentially linked to impaired synaptic plasticity. Genetic studies highlight the role of genes involved in NMDAR-dependent signaling and plasticity in schizophrenia. The dysconnection hypothesis also explains the interaction between different neurotransmitter systems, particularly the role of NMDAR-dependent plasticity in regulating DAergic and GABAergic functions. This interaction is crucial for understanding the pathophysiology of schizophrenia, including the dysregulation of prefrontal and striatal DAergic activity. The hypothesis further suggests that first-rank symptoms, such as delusions of control and hallucinations, may result from a failure of self-monitoring or corollary discharge mechanisms. These mechanisms are essential for distinguishing between self-generated and externally generated sensory inputs. Impairments in these mechanisms can lead to misattribution of inner speech to external sources, resulting in auditory hallucinations. The dysconnection hypothesis also addresses the clinical heterogeneity of schizophrenia, explaining how different symptoms may arise from variations in the expression of dysfunctional experience-dependent plasticity in the brain. Additionally, it accounts for the sex differences in onset and prevalence, which may be influenced by hormonal factors such as estrogens and androgens. Overall, the dysconnection hypothesis provides a comprehensive framework for understanding the pathophysiology of schizophrenia, linking abnormal synaptic plasticity to a wide range of clinical symptoms and offering a basis for future research and diagnostic approaches.