The synaptic cytoskeleton in development and disease

The cytoskeleton forms the backbone of neuronal architecture, sustaining its form and size, subcellular compartments and cargo logistics. The synaptic cytoskeleton can be categorized in the microtubule-based core cytoskeleton and the cortical membrane skeleton. While central microtubules form the fundamental basis for the construction of elaborate neuronal processes, including axons and synapses, cortical actin filaments are generally considered to function as mediators of synapse dynamics and plasticity. More recently, the submembranous network of spectrin and ankyrin molecules has been involved in the regulation of synaptic stability and maintenance. Disruption of the synaptic cytoskeleton primarily affects the stability and maturation of synapses but also secondarily disturbs neuronal communication. Consequently, a variety of inherited diseases are accompanied by cytoskeletal malfunctions, including spastic paraplegias, spinocerebellar ataxias, and mental retardation. Since the primary reasons for many of these diseases are still unknown model organisms with a conserved repertoire of cytoskeletal elements help to understand the underlying biological mechanisms. The astonishing technical as well as genetic accessibility of synapses in Drosophila has shown that loss of the cytoskeletal architecture leads to axonal transport defects, synaptic maturation deficits, and retraction of synaptic boutons, before synaptic terminals finally detach from their target cells, suggesting that similar processes could be involved in human neuronal diseases.