Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction.

Ashley L Comer,Giovanna Antognetti,Yenyu Liu,Kevin Liu Kot,Balaji Sriram,Thanh P H Nguyen,Lisa N Kretsge,Elena R Newmark,Tushare Jinadasa,James P Gilbert,Saraann Rosenthal,William W Yen,Borislav Dejanovic,Jungjoon Lee,Rhushikesh A Phadke,Frances S Hausmann,Alberto Cruz-Martín,Eric J Nestler

doi:10.1371/journal.pbio.3000604

Ashley L Comer, Giovanna Antognetti + Show 16 more

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https://doi.org/10.1371/journal.pbio.3000604

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Abstract

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

Highlights

Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by disruptions in brain connectivity that lead to an array of symptoms including psychosis and deficits in cognition and social interactions [1,2]
Using multiplex in situ hybridization (M-FISH), we showed that prefrontal cortex (PFC) neurons in postnatal day (P) 30 control mice express low levels of C4b transcript (S1A Fig), which was not present in tissue from C4b knock-out (C4 KO) mice (S1B Fig)
Within the same coronal section and cortical layer of the medial prefrontal cortex (mPFC), we identified excitatory L2/3 neurons that were either transfected (GFP+/calcium/calmodulin-dependent protein kinase type II subunit alpha [CaMKIIα]+) or untransfected (GFP−/CaMKIIα+) and compared the percent of C4 mRNA+ cell body areas (S1C Fig)

Summary

Introduction

Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by disruptions in brain connectivity that lead to an array of symptoms including psychosis and deficits in cognition and social interactions [1,2]. Understanding the underlying mechanisms of early social deficits in SCZ could reveal a therapeutic window to alter disease progression in these individuals. Patients with SCZ exhibit abnormal activity in the PFC during affective face perception and cognitive reappraisal [7,8,9]. These results are not surprising given the well-established role of the PFC in social behaviors [10,11,12]. The mechanisms that cause social deficits in SCZ are unclear, evidence suggests that dysfunction in the PFC correlates with symptom onset and severity [13]. It has been hypothesized that pathology in SCZ arises in part because of deficits in the pruning of cortical synapses, producing aberrant circuitry [14,15]

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