Understanding the role of synaptopodin and the spine apparatus in Hebbian synaptic plasticity - New perspectives and the need for computational modeling

- We review recently identified mechanisms of SP/SA-dependent LTP and LTD.
- We emphasize the need for detailed modeling of SP/SA-regulated Ca2+ dynamics and actin reorganization within spines.
- Reaction-diffusion models of endoplasmic reticulum will clarify unique Ca2+ dynamics in SA-containing spines.
- We suggest new simulations and experiments focusing on SP and small GTPases (Cdc42, RhoA) in PKA-mediated spine plasticity.
- Differences between simplified/complex and deterministic/stochastic models are discussed.

Synaptopodin (SP) is a proline-rich actin-associated protein essential for the formation of a spine apparatus (SA) in dendritic spines. The SA consists of stacks of smooth endoplasmic reticulum (sER) contiguous with the meshwork of somatodendritic ER. Spines of SP-deficient mice contain sER but no SA, demonstrating that SP is necessary for the assembly of ER cisterns into the more complex SA organelle. Although the SA was described decades ago, its function was difficult to investigate and remained elusive, in part because reliable markers for the SA were missing. After SP was identified as an essential component and a reliable marker of the SA, a role of SP/SA in hippocampal synaptic plasticity could be firmly established using loss-of-function approaches. Further studies revealed that SP/SA participate in the regulation of Ca2+-dependent spine-specific Hebbian plasticity and in activity-dependent changes in the spine actin cytoskeleton. In this review we are summarizing recent progress made on SP/SA in Hebbian plasticity and discuss open questions such as causality, spatiotemporal dynamics and complementarity of SP/SA-dependent mechanisms. We are proposing that computational modeling of spine Ca2+-signaling and actin remodeling pathways could address some of these issues and could indicate future research directions. Moreover, reaction-diffusion simulations could help to identify key feedforward and feedback regulatory motifs regulating the switch between an LTP and an LTD signaling module in SP/SA-containing spines, thus helping to find a unified view of SP/SA action in Hebbian plasticity.

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