Abstract
2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/− mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic “rich club” and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic “rich club” regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/− mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.
Highlights
Copy number variants (CNVs) are strongly implicated in the genetic etiology of schizophrenia (ScZ) and autism (ASD)
We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions
There was no evidence, in any region of interest (RoI), that sex significantly influenced the impact of Nrxn1α heterozygosity on cerebral metabolism
Summary
Copy number variants (CNVs) are strongly implicated in the genetic etiology of schizophrenia (ScZ) and autism (ASD). Population-based studies show that deletions at 2p16.3, involving heterozygous deletion of the NEUREXIN1 (NRXN1) gene, are associated with developmental delay, learning difficulties, and a dramatically increased risk of developing ASD (odds ratio = 14.9) (Matsunami et al 2013; Yuen et al 2017) and ScZ (odds ratio = 14.4) (Marshall et al 2017). Heterozygous NRXN1α deletions were first reported in Ketamine Restores Brain Connectivity in Neurexin1a+/− Mice Hughes et al 2359 small case studies of individuals with ASD (Friedman et al 2006) and ScZ (Kirov et al 2009) and have subsequently been identified in other cases (see Reichelt et al 2012 for review). Neurexins undergo extensive alternative splicing, which regulates their binding interactions, with isoforms being differentially expressed throughout the brain and across development (Ullrich et al 1995; Schreiner et al 2014; Treutlein et al 2014)
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