Stereotypy and precision of synaptic connectivity between brain regions, neuronal cell types, and subcellular compartments are general features of the nervous system, essential for the normal brain function. Due to its crystalline architectonic organization the cerebellum is one of the clearest examples of the striking selectivity of neuronal connectivity. Mossy and climbing fibers are the two major morphologically and functionally distinct types of afferents that innervate the cerebellum. Mossy fibers innervate granule cells, which in turn provide excitatory synaptic inputs to Purkinje cells; while climbing fibers form synapses exclusively with Purkinje cells. The timing and strength of mossy and climbing fiber connectivity determines the rate of Purkinje cell firing and thereby controls cerebellar output. Thus, temporal and spatial precision of connectivity as well as strength of afferent synapses is critical for cerebellar function.
Specificity of synaptic connectivity between neurons arises in a stepwise fashion during mammalian central nervous system development. Initial recognition between the afferent and the target neuron is followed by selective stabilization and growth of a subset of the initial contacts, and destabilization of others, crystallizing the mature connectivity pattern. The development of synaptic wiring plan involves a combination of synaptogenic and synapse destabilizing signaling events. Even though several synaptogenic factors have been identified in recent years, signaling mechanisms that trigger selective synapse removal are largely unknown.
While the initial exuberance and subsequent pruning of climbing fibers have been well characterized, much less is known about how cerebellar mossy fibers achieve precision of synaptic connectivity. The goal of my dissertation work has been to understand the developmental dynamics and molecular mechanisms that lead to emergence of precise mossy fiber to granule cell neural circuitry. Towards this goal, I have conducted a systematic analysis of the developmental pattern of mossy fiber connectivity in postnatal mice via in vivo DiI tracing followed by correlated light and electron microscopy, revealing that Purkinje cells serve as an intermediate target cell for mossy fiber afferents prior to the formation of mature mossy fiber-granule cell synaptic connections. In order to identify signals regulating these transient interactions, I have conducted a candidate screen, uncovering Bone Morphogenetic Protein 4 (BMP4) as a retrograde Purkinje cell derived negative regulator of mossy fiber axon growth, and a synapse-destabilizing signal.
Thus I propose that BMP4 plays a biphasic role during development to establish the mossy fiber synaptic target field: (1) during the first postnatal week, when mossy fibers extensively grow and arborize in the cerebellar cortex, BMP4 may restrict the length of branches extending to the Purkinje cell layer. (2) During postnatal weeks two and three, BMP4 may act as a synapse dispersal signal and contribute to the pruning of mossy fiber-Purkinje cell contacts.
|School Location:||United States -- New York|
|Source:||DAI-B 70/12, Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Cellular biology|
|Keywords:||Bone morphogenetic protein, Cerebellum, Fiber connectivity, Mossy fibers, Purkinje cells|
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