ABSTRACT The neurotropic virus Borna disease virus (BDV) persists in the central nervous systems of a wide variety of vertebrates and causes behavioral disorders. BDV represents an intriguing example of a virus whose persistence in neurons leads to altered brain function in the absence of overt cytolysis and inflammation. The bases of BDV-induced behavioral impairment remain largely unknown. To better characterize the neuronal response to BDV infection, we compared the proteomes of primary cultures of cortical neurons with and without BDV infection. We used two-dimensional liquid chromatography fractionation, followed by protein identification by nanoliquid chromatography-tandem mass spectrometry. This analysis revealed distinct changes in proteins implicated in neurotransmission, neurogenesis, cytoskeleton dynamics, and the regulation of gene expression and chromatin remodeling. We also demonstrated the selective interference of BDV with processes related to the adaptative response of neurons, i.e., defects in proteins regulating synaptic function, global rigidification of the cytoskeleton network, and altered expression of transcriptional and translational repressors. Thus, this work provides a global view of the neuronal changes induced by BDV infection together with new clues to understand the mechanisms underlying the selective interference with neuronal plasticity and remodeling that characterizes BDV persistence.