University of Tokyo scientists have singled out a protein that is responsible for "pruning" synapses to redirect nutrients and create stronger climbing fibers. The work was published in Neuron yesterday.
The pruning process is a necessity to create more refined and purposeful connections via a series of molecular mechanisms. However, sometimes genetic and environmental mutations can misguide this process and may eliminate too many synapses or not enough.
One type of neuron that contains these climbing fibers is called a Purkinje cell. "Among multiple climbing fibers innervating each Purkinje cell in the neonatal cerebellum, a single climbing fiber is strengthened and maintained throughout an animal's life, whereas the other climbing fibers are weakened and eventually eliminated," says Masanobu Kano, professor in the Department of Neurophysiology at the Graduate School of Medicine at the University of Tokyo.
Kano and his team found that progranulin, a protein known to be involved in certain forms of dementia, helps maintain the developing climbing fiber inputs, counteracting the initial elimination. In a mouse model without progranulin, they found that the climbing fibers were quickly eliminated and climbing fiber input overall was significantly reduced.
"Our results provide a new insight into the roles of progranulin in the developing brain," says Kano. "We will continue to search molecules involved in synapse elimination in the developing cerebellum and, ultimately, we want to elucidate entire signaling cascades for synapse elimination."
Image: Progranulin derived from Purkinje cells (PCs) counteracts synapse elimination and reinforces the strongest (winner) climbing fiber (CF). Progranulin acts on developing CF synapses from Postnatal day 11 to 16 independently of Semaphorin3A, another retrograde signaling molecule that counteracts CF synapse elimination. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. Loser CFs are maintained by progranulin-Sort1 signal and Semaphorin3A-PlexinA4 signal, but they are eventually pruned by "elimination signals" such as Semaphorin7A and brain-derived neurotrophic factor (BDNF). Image courtesy of 2018 Masanobu Kano.