Deciphering IGF1 and insulin signaling within a single dendritic spine in long term potential
The insulin superfamily of peptides are well-known to regulate metabolism by regulating blood sugar levels, but only recently insulin and insulin-like peptides were shown to be crucial nervous system function as well. Decreased brain insulin levels or dysfunctional insulin and insulin-like growth factor 1 signaling are related to impaired learning, memory, as well as age-related neurodegenerative diseases. However, it remains unknown whether insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are essential for synaptic plasticity and if so, when and how are they activated in dendritic spines during plasticity. To determine whether IR and IGF1R are required for plasticity, we assessed IR and IGF1R CRE-dependent knockout animals. We found that disruption of IGF1R or IR signaling in CA1 pyramidal neurons resulted in structural plasticity defects in those neurons. To further study the role of insulin and IGF1 signaling in plasticity, we developed fluorescence resonance energy transfer-based sensors for IGF1R and IR to measure the activity of the receptors during structural long-term potentiation (sLTP) in single spines. In response to sLTP induction, we found fast and sustained activation of IGF1R and IR in the stimulated spine. Elucidating insulin and IGF1 signaling mechanisms using two-photon fluorescence lifetime imaging microscopy in combination with new biosensors will potentially allow to develop novel drug approaches to treat Alzheimer’s disease or enhance learning and memory.