Insulin and IGF signaling in the brain: multilevel regulation of synaptic and network homeostasis

Insulin and insulin-like growth factor (IGF) signaling function as central regulators of synaptic homeostasis, bridging cellular metabolism with plasticity across molecular, synaptic, and network levels. Insulin signaling, is characterized as rapid and transient, and regulates energy metabolism, receptor trafficking, and short-term plasticity, whereas IGF signaling, with more sustained activity, supports neuronal survival, dendritic growth, and long-term remodeling. Together, they contribute to synaptic homeostasis through AMPAR/NMDAR modulation, astrocytic coupling, and activity-dependent scaling. Disruption of these regulatory processes has been associated with aberrant plasticity and altered network stability in Alzheimer's disease, epilepsy, and diabetic encephalopathy, highlighting their pathophysiological significance. This review synthesizes recent evidence to propose an integrative framework in which insulin and IGF signaling acts as a molecular hub linking metabolic state to synaptic homeostasis. Understanding this cross-scale regulation not only clarifies how metabolic disturbances lead to cognitive decline but also establishes a foundation for novel therapeutic strategies aimed at restoring neural network function in metabolic and neurodegenerative disorders.