Proper brain neuronal circuitry formation and synapse development is dependent on specific cues, either genetic or epigenetic, provided by the surrounding neural environment. Astrocytes are the main source of soluble and contact molecules that modulate neuronal morphogenesis. In the first part of this talking, we will discuss the role of astrocytes as mediators of thyroid hormones (T3 and T4) action in neuronal differentiation and synapse formation. The lack of thyroid hormones during childhood is associated with several impaired neuronal connections, cognitive deficits, and mental disorders. Although many of the thyroid hormones effects are mediated by astrocytes, the mechanisms underlying these events are still unknown. Here we provide evidence that astrocytes treated by T3 enhance neuronal maturation and number of synapses between cerebral cortex neurons in vitro. This event is mediated by increase in secretion of sulfate proteoglycans followed by a decrease in the levels of chondroitin sulfate proteoglycan by astrocytes in response to T3. In the second part of this talking, we will discuss the protective role of astrocytes against the toxicity of Aβ oligomers. Memory deficits in Alzheimer’s disease are thought to be the consequence of synapse damage instigated by these oligomers. We show here that astrocytes protect hippocampal neurons against synapse degeneration in vitro. Astrocyte-mediated neuroprotection was attributable to secreted soluble factors, yet under investigation. We argue that astrocytes are key mediators of hormone actions on cerebral cortex neuronal development and identified molecules and pathways involved synapse development that might be relevant to provide molecular-level rationale to understand synapse pathology.