Synapse-to-Nucleus Signaling in Neurodegenerative and Neuropsychiatric Disorders

Synapse-to-nucleus signaling is critical for converting signals received at synapses into transcriptional programs essential for cognition, memory, and emotion. This neuronal mechanism usually involves activity-dependent translocation of synaptonuclear factors from synapses to the nucleus resulting in regulation of transcriptional programs underlying synaptic plasticity. Acting as synapse-to-nucleus messengers, amyloid precursor protein intracellular domain associated-1 protein, cAMP response element binding protein (CREB)-regulated transcription coactivator-1, Jacob, nuclear factor kappa-light-chain-enhancer of activated B cells, RING finger protein 10, and SH3 and multiple ankyrin repeat domains 3 play essential roles in synapse remodeling and plasticity, which are considered the cellular basis of memory. Other synaptic proteins, such as extracellular signal-regulated kinase, calcium/calmodulin-dependent protein kinase II gamma, and CREB2, translocate from dendrites or cytosol to the nucleus upon synaptic activity, suggesting that they could contribute to synapse-to-nucleus signaling. Notably, some synaptonuclear factors converge on the transcription factor CREB, indicating that CREB signaling is a key hub mediating integration of synaptic signals into transcriptional programs required for neuronal function and plasticity. Although major efforts have been focused on identification and regulatory mechanisms of synaptonuclear factors, the relevance of synapse-to-nucleus communication in brain physiology and pathology is still unclear. Recent evidence, however, indicates that synaptonuclear factors are implicated in neuropsychiatric, neurodevelopmental, and neurodegenerative disorders, suggesting that uncoupling synaptic activity from nuclear signaling may prompt synapse pathology, contributing to a broad spectrum of brain disorders. This review summarizes current knowledge of synapse-to-nucleus signaling in neuron survival, synaptic function and plasticity, and memory. Finally, we discuss how altered synapse-to-nucleus signaling may lead to memory and emotional disturbances, which is relevant for clinical and therapeutic strategies in neurodegenerative and neuropsychiatric diseases.