The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain. : Angelman syndrome (AS) is a devastating monogenic human disorder that is nicely recapitulated in a mouse model. Reelin is an extracellular matrix protein that signals through specific lipoprotein receptors in the CNS and modifies synaptic function and memory formation. Reelin injected into the ventricles of the AS mouse model results in a recovery of the synaptic plasticity, spatial and associative learning and memory defects, thus, Reelin may be developed as a treatment for cognitive disorders.(Figure is included in full-text article.)