Changes in the molecular content of dendritic spines precede and are necessary for long-term potentiation (LTP), widely considered a cellular substrate of learning and memory. New receptors, channels, scaffolding proteins, and myriad other components must be delivered and incorporated into individual synapses to strengthen their connections with other neurons. As neurons mature they acquire elaborate, functionally specialized architectures, and as they become more complex so do the logistics of delivering these materials. An unresolved question is how these cargoes are delivered efficiently, but recent work from our lab and others suggests activity-dependent cytoskeletal coordination is instrumental in this. Thus, the first goal of this work has been to understand how the actin cytoskeleton preferentially directs transient entry of microtubules, and cargo transported along them, to individual synapses undergoing plasticity. While this line of research has merit in satisfying basic curiosity regarding the “gears and cogs” which drive our cognition, it is also important from a medical perspective, as the same mechanisms are vulnerable to dysregulation in common but debilitating diseases such as Alzheimer’s. This work has required the development of streamlined, versatile, genetically encoded tools to study the impact of functional mutations in mature neurons. The second overarching goal has been the refinement of this inducible knockdown-rescue (KDR) strategy for replacing endogenous protein of interest with experimental constructs. While originally conceived as a platform as a means of perturbing healthy cells to understand the effects of targeted mutations, in case of diseases with genetic etiology, we envision that with appropriate advances in therapeutic vectors the reverse is also quite possible. Though tools devised for basic research are rarely directly translatable to clinical application, we designed this technique to be easily portable and entirely vector agnostic. Therefore, future advances in viral therapeutics may be harnessed without undue complication, enhancing, rather than antiquating this strategy.