Abstract
Different afferent synapse populations interact to control the specificity of connections during neuronal circuit maturation. The elimination of all but one climbing-fiber onto each Purkinje cell during the development of the cerebellar cortex is a particularly well studied example of synaptic refinement. The suppression of granule cell precursors by X irradiation during postnatal days 4 to 7 prevents this synaptic refinement, indicating a critical role for granule cells. Several studies of cerebellar development have suggested that synapse elimination has a first phase which is granule cell-independent and a second phase which is granule cell-dependent. In this study, we show that sufficiently-strong irradiation restricted to postnatal days 5 or 6 completely abolishes climbing fiber synaptic refinement, leaving the olivo-cerebellar circuit in its immature configuration in the adult, with up to 5 climbing fibers innervating the Purkinje cell in some cases. This implies that the putative early phase of climbing fiber synapse elimination can be blocked by irradiation-induced granule cell loss if this loss is sufficiently large, and thus indicates that the entire process of climbing fiber synapse elimination requires the presence of an adequate number of granule cells. The specific critical period for this effect appears to be directly related to the timing of Purkinje cell and granule cell development in different cerebellar lobules, indicating a close, spatiotemporal synchrony between granule-cell development and olivo-cerebellar synaptic maturation.
Highlights
The refinement of neuronal circuits during development is critical to their subsequent function; abnormalities in this process can result in neurodevelopmental disorders
This model has been reinforced by experiments with transgenic mice having faulty parallel fiber (PF) postsynaptic signaling. In these mice, lacking the type-1 metabotropic glutamate receptor[21] or one of its downstream signaling molecules (Gαq[22], PLCβ423, PKCγ24,25), climbing fibre afferents (CFs) synapse elimination is not completely blocked, with 30–40% of Purkinje cells (PCs) multiply-innervated and with an average of 2.5 climbing fibers per Purkinje cell (CFs/PC) in the adult. This is less than the average of 3.5–4 CFs per PC seen in early development; these observations of partially-disrupted CF synapse elimination supported the hypothesis of an early phase of granule cells (GCs)-independent synapse elimination[20,25]
We determined (1) the percentage of PCs multiply innervated by CFs; and (2) the index of multiple innervation m, which is the number of steps in spontaneous and evoked CF-excitatory postsynaptic potentials (EPSPs)
Summary
The refinement of neuronal circuits during development is critical to their subsequent function; abnormalities in this process can result in neurodevelopmental disorders (eg autism spectrum disorder, schizophrenia, etc). This model has been reinforced by experiments with transgenic mice having faulty PF postsynaptic signaling In these mice, lacking the type-1 metabotropic glutamate receptor[21] or one of its downstream signaling molecules (Gαq[22], PLCβ423, PKCγ24,25), CF synapse elimination is not completely blocked, with 30–40% of PCs multiply-innervated and with an average of 2.5 CFs/PC in the adult. Suppression of GCPs by X-irradiation allows the experimenter to control precisely the time and the extent of GCP suppression while leaving already-differentiated GCs not visibly affected[26,27] (see Materials and Methods section) With this approach, Mariani et al.[28] showed that the GCPs suppressed by irradiation during a critical period (P4-P7) are necessary to initiate CF synapse elimination; their protocol allowed maintenance of multi-innervation at almost the maximum developmental level (3.5 ± 0.85 CFs per PC18)
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