Abstract
Insulin-like growth factor II (IGF2) enhances memory in rodents via the mannose-6-phosphate receptor (M6PR), but the underlying mechanisms remain poorly understood. We found that human IGF2 produces an enhancement of both synaptic transmission and neurite outgrowth in the marine mollusk Aplysia californica. These findings were unexpected since Aplysia lack the mammal-specific affinity between insulin-like ligands and M6PR. Surprisingly, this effect was observed in parallel with a suppression of neuronal excitability in a well-understood circuit that supports several temporally and mechanistically distinct forms of memory in the defensive withdrawal reflex, suggesting functional coordination between excitability and memory formation. We hypothesize that these effects represent behavioral adaptations to feeding that are mediated by the endogenous Aplysia insulin-like system. Indeed, the exogenous application of a single recombinant insulin-like peptide cloned from the Aplysia CNS cDNA replicated both the enhancement of synaptic transmission, the reduction of excitability, and promoted clearance of glucose from the hemolymph, a hallmark of bona fide insulin action.
Highlights
Insulin and related peptides are among the most conserved signaling molecules in the animal kingdom[1,2,3]
IGF2 promotes the induction of long-term facilitation (LTF) when combined with 5HT
We have demonstrated an unusual combination of effects exerted by IGF2 on Aplysia sensory neurons
Summary
Insulin and related peptides are among the most conserved signaling molecules in the animal kingdom[1,2,3]. Memory enhancement required a different transmembrane effector unrelated to insulin-like receptors This protein, generally termed the cation-independent mannose-6-phosphate receptor (M6PR), displays multiple ligand affinities and in certain mammals is known as the IGF2 receptor (IGF2R) owing of its evolutionarily novel affinity to IGF215–17. One well-characterized aspect of Aplysia behavior is defensive withdrawal of the gill, siphon, or tail upon mechanical stimulation[22,26,27,28] Much of this response is controlled by a monosynaptic glutamatergic circuit consisting of a mechanosensory neuron (SN), either in the ventrocaudal sensory cluster of the pleural gangion, or in the LE cluster of the abdominal ganglion, and a motor neuron (MN). Using a simplified preparation consisting of pleural SNs cultured with or without a postsynaptic partner (L7 motoneuron), we show in the present study that IGF2 in Aplysia promotes long-term synaptic facilitation and neurite growth, but simultaneously (and unexpectedly) reduces neuronal excitability, a combination of effects that we propose is associated with the homeostatic functions of Aplysia’s insulin-like system
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