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 Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 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 Negr1−/− 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 Negr1−/− hippocampi. Behaviorally, Negr1−/− mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 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, Negr1−/− mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.
Highlights
Distinct psychiatric disorders such as schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BP), autism spectrum disorders (ASD), and attention-deficit hyperactivity disorder (ADHD) share a common genetic etiology with a diverse set of partially overlapping symptoms[1]
For the initial screening of sub-regional organisation in Negr1−/− mouse brain we carried out an immunostaining detecting neurofilament
We show that Negr1−/− mice possess neuroanatomical and behavioral endophenotypes which are related to the core diagnostic domains of several psychiatric disorders like SCZ, ASD and ADHD
Summary
Distinct psychiatric disorders such as schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BP), autism spectrum disorders (ASD), and attention-deficit hyperactivity disorder (ADHD) share a common genetic etiology with a diverse set of partially overlapping symptoms[1]. Impaired cortical-subcortical integrity has been involved in the development of psychiatric disorders like SCZ4, MDD5, ASD6, BP7 and in the etiology of psychological and cognitive symptoms in neurodegenerative disorders like Alzheimer’s disease (AD)[8] and Parkinson’s disease (PD)[9]. Neuroimaging studies indicate common cross-disorder volumetric alterations of cortical and subcortical brain regions, the most www.nature.com/scientificreports/. Large-scale genome-wide association studies (GWAS) indicate polymorphisms present in the NEGR1 gene to be associated with the risk for SCZ18, MDD19 and AD20. Increased level of NEGR1 transcripts has been reported in the DLPFC of patients with MDD in comparison with healthy controls[28]. Specific variants in NEGR1 gene locus have been implicated in human obesity, body mass index[32,33] and psychological traits commonly linked with eating disorders[34]. The body mass phenotype could be related to the interaction of NEGR1 with the Niemann-Pick disease Type C2 (NPC2) protein that alters cholesterol transport[35]
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