Formation, stability, and competition in dendritic proto-spines

Over 80 % of excitatory synapses in the mammalian brain terminate on dendritic spines, which support key functions of memory storage and computation. Despite the neurodevelopmental and computational implications of spine formation, little is known about the interplay of physical and chemical signaling mechanisms that govern spine initiation. We developed a physics-based model for the formation, stability, and placement of membrane protrusions (proto-spines) triggered by membrane-bending proteins such as IRSp53, and activated by neurotransmitter inputs. We identify two distinct proto-spine energy manifolds depending on the concentration of activated IRSp53, causing shallow and sharp geometries respectively. The sharp proto-spines exhibit properties of wave-pinning models, including stimulus-local formation, positional stability, and merging, but unlike the wave-pinning model they also exhibit competition. We linked the physics-based model to a mass-action chemistry model of neurotransmitter-driven signaling pathway activation of IRSp53 to simulate proto-spine formation in response to neurotransmitter stimulus patterns. Multiple proto-spines compete for IRSp53, leading to inter-spine spacing of 1 - 3 µm , similar to experiments. Correlated and spatially clustered synaptic input enhances proto-spine lifetime and density compared to non-correlated stimuli. Finally, we tested the effects of autism spectrum disorder-related mutations in spine-formation signaling, leading to altered RhoGEF activity. We found that elevated RhoGEF activity increased proto-spine density and reduced their lifetime, consistent with ASD phenotypes. Overall, our analysis shows that the interplay between membrane bending mechanics and reaction-diffusion chemistry creates rich proto-spine dynamics and concisely captures key features of early spine formation. Significance Statement Dendritic spines mediate most of the excitatory neurotransmission in the brain, and alterations in their shape and distribution on the dendrite are correlated with neuro-developmental and neuro-degenerative conditions. We model membrane mechanics and chemical signaling to show that spine precursors arise as self-stabilizing membrane protrusions due to the binding of membrane-bending proteins. Spine precursors act as nucleation sites for spine-building proteins, and hence their stability, placement, and signaling impacts late-stage spine maturation. These proto-spines compete with each other for bending proteins, and we connect this interplay with signaling chemistry that triggers new spines immediately below sites of transmitter release. We find that aberrant signaling in neurological disease alters proto-spine competition, life-time and placement.