NRG3 is a brain-enriched neuregulin that functions as a direct ligand for the ERBB4 tyrosine kinase receptor 1. Upon binding, NRG3 stimulates ligand-dependent tyrosine phosphorylation and activation of ERBB4, initiating intracellular signaling cascades 2. The gene undergoes complex alternative splicing producing multiple isoforms (classes I-IV) with distinct temporal and tissue-specific expression patterns during human neocortical development and aging 3. NRG3 plays critical roles in early mammary morphogenesis and neural development 1. NRG3 signaling is implicated in multiple neurological and psychiatric disorders. Genetic variants in NRG3 associate with schizophrenia risk, with polymorphism rs10748842 predicting elevated expression of developmentally regulated isoforms in the prefrontal cortex 2. Additionally, NRG3 variants correlate with Alzheimer disease risk and age of onset 4, and increased expression of specific isoforms appears in bipolar disorder and major depression 3. In schizophrenia, NRG3 rs10748842 associates with cognitive deficits, particularly attention impairment 5. The NRG3-ERBB4 signaling pathway participates in epilepsy pathogenesis 6. Mechanistically, mature NRG3 undergoes transcytosis into axons via BACE1-dependent cleavage and accumulates at presynaptic terminals through trans-synaptic retention via postsynaptic ERBB4 7.