Effects of insulin-like growth factor I on climbing fibre synapse elimination during cerebellar development

Functional neural circuit formation includes the process by which redundant synaptic connections formed earlier during development are subsequently eliminated. We report that insulin-like growth factor I (IGF-I) is a candidate factor that influences the developmental transition from multiple to mono innervation of cerebellar Purkinje cells (PCs) by climbing fibres (CFs). Continuous local application of exogenous IGF-I to the mouse cerebellum by means of ethylene-vinyl acetate copolymer (Elvax) significantly increased the degree of multiple CF innervation, when the IGF-I containing Elvax was implanted at postnatal day 8 (P8). In contrast, the IGF-I application starting at P12 had no effect on CF innervation. Conversely, continuous local application of antisera against IGF-I and its receptor significantly decreased the degree of multiple CF innervation when the application started at P8. We found that chronic treatment of exogenous IGF-I from P8 significantly enhanced the CF-mediated excitatory postsynaptic currents (CF-EPSCs). This effect was manifest for the smaller CF-EPSCs but not for the largest CF-EPSC of the multiple-innervated PCs. Conversely, chronic application of antisera from P8 caused attenuation of the largest CF-EPSCs. Other parameters for basic synaptic functions and cerebellar morphology were largely normal after the IGF-I or antisera treatment. These results suggest that IGF-I enhances the strength of developing CF synapses and may promote their survival, whereas the shortage of IGF-I impairs the development of CF synapses and, as a result, may facilitate their elimination. Thus, IGF-I is a potentially important factor among various signalling molecules that can influence CF synapse elimination during cerebellar development.