Abstract
A recent report suggested Complement 4 (C4A) gene copy numbers (GCN) as risk factors for schizophrenia. Rodent model showed association of C4 with synaptic pruning suggesting its pathophysiological significance (Sekar, A. et al. (2016)). We, therefore, predicted that C4A GCN would be positively correlated with neuropil contraction in the human brain among schizophrenia patients showing more prominent correlations in ventral regions among young adults and dorsal regions among adolescents since neuromaturation progresses dorsoventrally. Whole-brain, multi-voxel, in vivo phosphorus magnetic resonance spectroscopy (31P MRS) assessed neuropil changes by estimating levels of membrane phospholipid (MPL) precursors and catabolites. Increased MPL catabolites and/or decreased MPL precursors indexed neuropil contraction. Digital droplet PCR-based assay was used to estimate C4A and C4B GCN. We evaluated two independent cohorts (young adult-onset early-course schizophrenia (YASZ = 15) and adolescent-onset schizophrenia (AOSZ = 12) patients), and controls matched for each group, n = 22 and 15, respectively. Separate forward stepwise linear regression models with Akaike information Criterion were built for MPL catabolites and precursors. YASZ cohort: Consistent with the rodent model (Sekar, A. et al. 2016)), C4A GCN positively correlated with neuropil contraction (increased pruning/decreased formation) in the inferior frontal cortex and inferior parietal lobule. AOSZ cohort: C4A GCN positively correlated with neuropil contraction in the dorsolateral prefrontal cortex and thalamus. Exploratory analysis of C4B GCN showed positive correlation with neuropil contraction in the cerebellum and superior temporal gyrus among YASZ while AOSZ showed neuropil contraction in the prefrontal and subcortical structures. Thus, C4A and C4B GCN are associated with neuropil contraction in regions often associated with schizophrenia, and may be neuromaturationally dependent.
Highlights
Schizophrenia is a severe brain disorder which costs over$155 billion a year in the United States[1]
We examined the relationship of C4 gene copy numbers (GCN) with neuropil contraction/expansion in a human context within two independent cohorts of schizophrenia patients and healthy controls (HC)
We examined two independent cohorts–young adultonset schizophrenia (YASZ) cohort (n = 15) and adolescent-onset schizophrenia (AOSZ) patients (n = 12)and two HC cohorts age-matched for each group (n = 22 and 15, respectively)
Summary
Schizophrenia is a severe brain disorder which costs over$155 billion a year in the United States[1]. Available treatments are symptomatic leading to poor long-term social outcome[2,3,4,5]. One of the neurodevelopmental models that propose excessive loss of synapses[6] may be one such mechanism. Convergent animal[7,8], human developmental[9], neuroimaging[10,11], postmortem[12,13], and computational modeling[14,15] data suggest that increased neuropil loss predates[16,17,18,19,20,21,22,23] and continues. Prasad et al Translational Psychiatry (2018)8:134 after the onset of psychosis[24,25], and may predict short-term outcome[26]. The genetic underpinnings of excessive synaptic pruning are poorly understood in humans
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