A molecular carrot-and-stick approach to wiring the brain

A versatile molecule that comes in two flavors, helps fine-tuning synaptic connections in the developing brain. That is the conclusion of a study by the Netherlands Institute for Neuroscience published in Cell Reports. The discovery by the Christian Lohmann group offers new insights into developmental disorders such as autism, in which neural connections are disrupted, and may lead to a better treatment of the disease.

BDNF

Neurons in the developing brain generate precisely connected networks already before the senses become active. In particular, brain-derived neurotrophic factor (BDNF) has been known to stabilize and potentiate synaptic connections between nerve cells. However, nerve cells also generate a precursor of BDNF (proBDNF) that can depress synaptic function.

This study indicates that an antagonistic interaction of BDNF and proBDNF controls the precise arrangement of synapses in developing neurons. While proBDNF punishes desynchronized synapses, it is converted to BDNF by the enzyme matrix metalloproteinase-9 (MMP9) at locally synchronized synapses to reward and maintain synapses that contribute to synaptic clusters.

Clustering

The highest degree of precision of synaptic inputs on hippocampal and cortical neurons is represented by synaptic clustering: the co-arrangement of synapses with similar activity patterns and high synchronicity into short stretches of dendrites. Synaptic clustering requires spontaneous neuronal activity to develop.

The researchers observed that both proBDNF and BDNF, as well as their respective receptors, are required for synaptic clustering. They state that endogenous BDNF is present at and boosts clustered synapses, whereas native proBDNF localizes to and depresses out-of-sync synapses.

Together, these data delineate an efficient plasticity mechanism where proBDNF and mature BDNF establish synaptic clustering through antagonistic modulation of synaptic transmission.