Schizophrenia (SZ) is a devastating psychiatric disorder affecting about 1% of the world’s population. Social-cognitive impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social-cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the whole-brain level, an abnormal activation of social brain regions and interregional dysconnectivity within social-cognitive brain networks have been identified as major contributors to these symptoms. At the cellular and subcellular levels, an interplay between oxidative stress, neuroinflammation and N-methyl-D-aspartate receptor hypofunction is thought to underly SZ pathology. However, it is not clear how these molecular processes are linked with interregional dysconnectivity in the genesis of social-cognitive symptoms. Here, we aim to bridge the gap between macroscale (connectivity analyses) and microscale (molecular and cellular mechanistic) knowledge by proposing impaired myelination and the disinhibition of local microcircuits as possible causative biological pathways leading to dysconnectivity and abnormal activity of the social brain. Furthermore, we recommend electroencephalography as a promising translational technique that can foster pre-clinical drug development and discuss attractive drug targets for the treatment of social-cognitive symptoms in SZ.

Schizophrenia (SZ) is a devastating psychiatric disorder affecting 1% of the world population. Social cognition impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the cellular level, an interplay between oxidative stress, inflammation and N-methyl-D-aspartate (NMDA) receptor hypofunction is thought to underly SZ pathology. At the whole-brain level, a reduced activation of social brain regions and a decrease in inter-regional connectivity within the social brain have been identified as major contributors to social cognition impairment in SZ. However, it is not clear how these pathological processes at the cellular level lead to whole-brain dysconnectivity in the origin of social cognition impairments. Aiming at bridging the gap between microscale (molecular and cellular mechanisms) and macroscale (whole-brain) knowledge, in this review, we propose impaired myelination and glial cell death in white matter tracts as possible intermediate biological pathways. Furthermore, we recommend electroencephalography as a promising translational technique that could revolutionize pre-clinical drug development research and discuss promising drug targets for the treatment of SZ social cognition impairment.