Scientists have identified a molecule that aids a crucial "pruning" process in the brain that, if malfunctioning, could lead to disorders such as autism and dementia.

As the brain develops in utero and in early life, neurons and their connecting synapses branch out rapidly - like a tree. Over time, these connections become more refined and purposeful via a series of molecular mechanisms that prune the connections. Like a gardener trims a tree, weaker branches are discarded to redirect nutrients to help nurture the stronger branches.

However, genetic and environmental mutations can misguide this process and eliminate far too many synapses or not nearly enough. Either extreme can result in a myriad of neuropsychiatric disorders from autism spectrum disorder to schizophrenia to dementia. The authors published their results in the journal Neuron.

In a typically developing brain, a type of neuron called a Purkinje cell is furnished with climbing fibers. "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," senior author says. "Our goal was to identify a new molecule involved in strengthening and maintaining single climbing fiber inputs."

The team found that progranulin - a protein known to be involved in certain forms of dementia - also works to maintain developing climbing fiber inputs, counteracting the initial elimination. They studied a mouse model engineered without progranulin and found that climbing fibers were more quickly eliminated and climbing fiber input overall was significantly reduced.

Authors show that progranulin derived from purkinje fibers acts retrogradely onto its putative receptor Sort1 on climbing fibers. This effect is independent of semaphorin 3A, another retrograde signaling molecule that counteracts CF synapse elimination.

Authors propose that progranulin-Sort1 signaling strengthens and maintains developing CF inputs, and may contribute to selection of single “winner” climbing fibers that survive synapse elimination.

"Our results provide a new insight into the roles of progranulin in the developing brain," says senior author. "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."

Although the researchers do not yet know how to effectively manipulate the molecule, it's possible that progranulin signaling may be a potential therapeutic target for neuropsychiatric disorders.

http://www.cell.com/neuron/fulltext/S0896-6273(18)30021-7