Advances in neurotransmitter-mediated prefrontal circuitry in depression

Depression, a highly prevalent neuropsychiatric disorder characterised by persistently low mood and anhedonia, poses a severe threat to human health. The prefrontal cortex (PFC), a core brain region governing emotional and cognitive regulation, exhibits dysfunctional neural circuitry that constitutes a key mechanism in the pathogenesis of depression. This article reviews neurotransmitter-mediated PFC-related neural circuits in depression. Dopamine (DA) modulates reward processing and cognitive functions through circuits such as the ventral tegmental area-PFC and PFC-nucleus accumbens. Aberrant receptor function within these circuits leads to imbalanced excitability of PFC pyramidal neurons. Glutamate (Glu), the primary excitatory neurotransmitter, mediates synaptic transmission via N-methyl-d-aspartate/ α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in circuits including the medial PFC (mPFC) and basolateral amygdala. Its dysregulation disrupts the excitation–inhibition balance within the PFC. Serotonin (5-hydroxytryptamine [5-HT]) regulates inhibitory neurons through the mPFC-dorsal raphe nucleus circuit, and reduced 5-HT levels exacerbate emotional disturbances. Gamma-aminobutyric acid (GABA) maintains the stability of PFC circuits via parvalbumin/somatostatin interneurons, and its dysfunction causes excessive excitation. Furthermore, complex interactions exist between neurotransmitters; for instance, DA and Glu synergistically regulate synaptic plasticity, whereas 5-HT and GABA coordinate the inhibitory balance. This review identifies unresolved issues in current research, including unclear mechanisms and heterogeneity. Future studies should explore neurotransmitter interactions and individual differences to provide a theoretical basis for the precise diagnosis and treatment of depression.