Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

Abstract

Neuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of <i>Negr1</i> deficiency on brain morphology, neuronal properties and social behavior of mice. <i>In situ</i> hybridization shows <i>Negr1</i> expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in <i>Negr1</i>⁻/⁻ mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in <i>Negr1</i>⁻/⁻ hippocampi. Behaviorally, <i>Negr1</i>⁻/⁻ mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, <i>Negr1</i> deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, <i>Negr1</i>⁻/⁻ mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.