Climbing fiber development: do neurotrophins have a part to play?

The climbing fiber input to the cerebellum is crucial for its normal function but those factors which control the development of this precisely organized pathway are not fully elucidated. The neurotrophins are a family of peptides, which have many roles during development of the nervous system, including the cerebellum. Since the cerebellum and inferior olive express neurotrophins and their receptors, we propose that neurotrophins are involved in the regulation of climbing fiber development. Here we review the temporo-spatial expression of neurotrophins and their receptors at key ages during climbing fiber development and then examine evidence linking neurotrophins to climbing fiber development, including some of the intracellular pathways involved. During prenatal development the expression of neurotrophins in the hindbrain coupled with their function in neurogenesis and migration, is consistent with a role of NT3 in inferior olivary genesis. Subsequently, cerebellar expression of two neurotrophins, NT3 and NT4, is concurrent with olivary receptor expression and the time of olivary axonal outgrowth and this continues postnatally during early climbing fiber synaptogenesis on Purkinje cells. The expression-pattern of neurotrophins changes with age, with falling NGF, NT3 and NT4 but increasing granule cell BDNF. Importantly, olivary expression of neurotrophin receptors, and therefore climbing fiber responsiveness to neurotrophins, falls specifically during maturation of the climbing fiber-Purkinje cell synapse. The function of BDNF is less certain, but experimental studies indicate that it has a role in climbing fiber innervation of Purkinje cells, particularly synaptogenesis and synaptic plasticity. Its importance is highlighted by the overlap of BDNF signalling with several cellular pathways, which regulate climbing fiber maturation. From the data presented, we propose not only that neurotrophins are involved in climbing fiber development, but also that several act in a specific temporal order.