Female sexual maturation requires erythroblastosis B (erbB)4 signaling in hypothalamic astrocytes; however, the mechanisms by which erbB4 contributes to this process are incompletely understood. Here we show that SynCAM1, a synaptic adhesion molecule with signaling capabilities, is not only expressed highly in neurons, but also in hypothalamic astrocytes and is functionally associated with erbB4 receptor activity. Whereas SynCAM1 expression is diminished in astrocytes with impaired erbB4 signaling, ligand-dependent activation of astroglial erbB4 receptors results in rapid association of erbB4 with SynCAM1 and activation of SynCAM1 gene transcription. To determine whether astrocytic SynCAM1-dependent intracellular signaling is required for normal female reproductive function, we generated transgenic mice that express in an astrocyte-specific manner a dominant-negative form of SynCAM1 lacking the intracellular domain. The mutant protein was correctly targeted to the cell membrane and was functionally viable as shown by its ability to block intracellular calcium/calmodulin-dependent serine protein kinase redistribution, a major SynCAM1-mediated event. Dominant-negative-SynCAM1 female mice had a delayed onset of puberty, disrupted estrous cyclicity, and reduced fecundity. These deficits were associated with a reduced capacity of neuregulin-dependent erbB4 receptor activation to elicit prostaglandin E2 release from astrocytes and GnRH release from the hypothalamus. We conclude that one of the mechanisms underlying erbB4 receptor-mediated facilitation of glial-neuronal interactions in the neuroendocrine brain involves SynCAM1-dependent signaling and that this interaction is required for normal female reproductive function.