Insulin-like growth factor-I (IGF-I) has trophic and plastic effects on neurons and glial cells and modulates neuroendocrine events by acting at the level of the hypothalamus. IGF-I and estrogen signaling interact to regulate in vitro hypothalamic neuronal survival and differentiation. In vivo, IGF-I levels fluctuate in the rat hypothalamic arcuate nucleus during the estrous cycle in parallel with a phasic remodeling of synaptic contacts and glial cell processes. Both the fluctuation of IGF-I levels and the synaptic and glial changes are induced by estrogen. The possible role of IGF-I in the regulation of arcuate nucleus synaptic plasticity has been assessed in the present study by intracerebroventricular administration to cycling female rats of a specific IGF-I receptor antagonist. In agreement with previous findings, the number of synaptic inputs to arcuate neuronal somas in control rats showed a significant decrease between the morning of proestrus and the morning of estrus. This decline in synaptic inputs and the accompanying increase in glial ensheathing of neuronal somas were blocked by the IGF-I receptor antagonist. In contrast, the IGF-I receptor antagonist did not affect the basal number of synapses or the morphology of synaptic terminals or length of the synaptic contacts. These findings indicate that IGF-I receptor activation may be involved in the phasic remodeling of arcuate nucleus synapses during the estrous cycle. Res.