Turning a growth cone into a synapse: Molecular and cellular mechanisms underlying the wiring of neurons

Abstract

The development and wiring of the nervous system are highly organised and regulated processes depending on a precise timing to connect the right paths. To connect with designated targets, neurons form an axon which extends until it reaches its synaptic partners. For this, neurons possess an enormous growth capacity and grow rapidly during development. The cytoskeleton, actin filaments, microtubules and intermediate filaments, are the conductor of these developmental processes. However, during neuronal maturation the growth capacity is lost and neurons fail to regenerate. This is attributed to a growth inhibiting environment but also to a low intrinsic growth propulsion of mature neurons. In young neurons, a dense actin network in minor neurite tips restricts the outgrowth of the axon. Increasing actin dynamics allows axonal outgrowth. <br/> Here, I investigated in cultured hippocampal neurons whether increased stabilisation of actin filaments and attenuated actin dynamics contribute to the decline of growth capacity and reduce growth and regeneration of mature neurons. By manipulating different aspects of actin dynamics, pharmacologically and genetically, I showed that young neurons depend on precisely regulated actin dynamics to drive axon growth, while mature neurons are less dependent on actin to drive growth. I propose that neurons switch their mode of growth in the course of development from a more actin-dependent to a rather actin-independent way of growth. The outgrowth of the axon is controlled by contractile actomyosin that limits neurite extension. The axon escapes this growth restriction, while the other neurites remain growth-restricted, to maintain a polarised morphology. <br/> I found that reduced actin dynamics in mature neurons seem not to be the reason for reduced growth capacity of mature neurons. Instead, the onset of the transmission of electrical signals correlates with the decline in growth rates, supporting the hypothesis that growth and transmission activity are mutually exclusive. Chronic depolarisation negatively affected the growth of polarised neurons. Thus, the underlying mechanisms by which physiological electrical activity negatively affects the ability of CNS neurons to grow need to be addressed in the future.