Abstract
The function of neuronal networks relies on selective assembly of synaptic connections during development. We examined how synaptic specificity emerges in the pontocerebellar projection. Analysis of axon-target interactions with correlated light-electron microscopy revealed that developing pontine mossy fibers elaborate extensive cell-cell contacts and synaptic connections with Purkinje cells, an inappropriate target. Subsequently, mossy fiber–Purkinje cell connections are eliminated resulting in granule cell-specific mossy fiber connectivity as observed in mature cerebellar circuits. Formation of mossy fiber-Purkinje cell contacts is negatively regulated by Purkinje cell-derived BMP4. BMP4 limits mossy fiber growth in vitro and Purkinje cell-specific ablation of BMP4 in mice results in exuberant mossy fiber–Purkinje cell interactions. These findings demonstrate that synaptic specificity in the pontocerebellar projection is achieved through a stepwise mechanism that entails transient innervation of Purkinje cells, followed by synapse elimination. Moreover, this work establishes BMP4 as a retrograde signal that regulates the axon-target interactions during development.
Highlights
The specificity of synaptic connectivity in the central nervous system is a prerequisite for brain function
How neuronal processes select their appropriate target cells from an array of interaction partners is poorly understood. We have addressed this question for the axons emerging from the pontine gray nucleus, a major brainstem nucleus that relays information between the cortex and the cerebellum, a brain area responsible for the control of skilled movements and emotional processing
We identify bone morphogenetic protein 4 (BMP4) as a regulator of these inappropriate mossy fiber-Purkinje cell contacts
Summary
The specificity of synaptic connectivity in the central nervous system is a prerequisite for brain function. The neuronal circuits in the vertebrate cerebellum represent a remarkable example of wiring specificity. This was first recognized by Santiago Ramon y Cajal when he chose cerebellar circuits as revealed by the Golgi method for his early studies on brain organization (discussed in [1]). In its simplest form, the cerebellar microcircuit integrates input from two afferent classes—climbing and mossy fibers. In the IGL, mossy fibers form synapses on Golgi cells, a class of inhibitory interneurons that provide feed-forward inhibition in the cerebellar circuit. Climbing and mossy fiber information is integrated in Purkinje cells and transduced via cerebellar efferent projection neurons in the deep cerebellar nuclei. The molecular mechanisms regulating synapse specificity for most circuits in the mammalian brain have remained obscure
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