Transmembrane isoforms of Neuregulin-1 (NRG1) contain an extracellular domain, a transmembrane domain, and a highly conserved intracellular domain. Several recent findings suggest a role of NRG1 signaling in synaptic maintenance and possibly neurodegenerative diseases. The extracellular domain of NRG1 binds to the ErbB family of receptor tyrosine kinases to activate signaling cascades in target cells. This “forward signaling” pathway regulates the expression of receptors for several neurotransmitters. We have recently found that the intracellular domain of NRG1 (NRG1-ICD) translocates into the nucleus where it regulates gene expression. Specifically, this “backward signaling” pathway, which is enhanced by synaptic activity, up-regulates postsynaptic density protein 95 (PSD- 95) expression. PSD-95 is a scaffolding protein enriched in post-synaptic structures. NRG1-ICD enhances the transcriptional activity of the PSD-95 promoter by binding to a zinc-finger transcription factor, Eos. Up-regulation of PSD-95 could contribute to normal physiological processes, such as synaptic plasticity for learning and memory, it may also be associated with neuronal excitotoxicity under pathological conditions. NRG1-ICD is specifically associated with neuritic plaques in the brain of patients with Alzheimers disease. Loss of synaptic connections is found in the brain of Alzheimers disease. Therefore, further studies of the signal transduction pathways activated by NRG1-ICD will provide insight into the molecular mechanisms underlying learning and memory, as well as a basis for possible clinical interventions for age-related neurodegeneration diseases.