From synapse to system: mechanistic pathways of neural signaling dysfunction in psychiatric disorders

Psychiatric disorders are increasingly viewed as network-level brain diseases resulting from disruptions in neural signaling across various hierarchies, including molecular, synaptic, circuit, and systems levels. Evidence indicates that receptor dysregulation, abnormal intracellular pathways, and changes in ion channel activity lead to widespread network dysconnectivity, resulting in cognitive, emotional, and behavioral deficits. This review integrates advancements in genomics, transcriptomics, connectomics, and computational modeling to establish a framework for understanding signaling abnormalities in major psychiatric disorders. Further, this study investigates essential molecular and cellular processes such as synaptic plasticity, receptor-mediated communication, intracellular signaling cascades, and neuroimmune interactions, and connects these to disturbances in oscillatory dynamics, circuit architecture, and overall brain network organization. Additionally, neuroimaging and graph-theoretic studies consistently demonstrate an excitation–inhibition imbalance, atypical synaptic pruning, impaired oscillatory synchrony, and maladaptive connectivity within networks, including the default mode, salience, and fronto-limbic systems, across schizophrenia, depression, bipolar disorder, anxiety, and autism spectrum disorders. Moreover, genetic and epigenetic variations in signaling genes, such as CACNA1C, GRIN2B, and DISC1, along with developmental and environmental factors, contribute to network vulnerability and clinical heterogeneity. Emerging artificial intelligence and multimodal integration methods facilitate the identification of individualized “signaling fingerprints,” which connect molecular perturbations to systems-level dysfunction. This research enhances precision psychiatry and guides targeted interventions based on neuromodulation, molecular mechanisms, and biomarkers.