Abstract
BackgroundThe current study was to explore how disruption of specific molecular circuits in the cerebral cortex may cause large-scale brain structure deficits and behavior changes via a translational study in conditional Erbb4 mutant mice and patients with schizophrenia.MethodsWe conducted prepulse inhibition (PPI) and brain structural and diffusion magnetic resonance imaging (MRI) scans in 27 mice with ErbB4 knockout in parvalbumin (PV) interneurons and 23 age, sex-matched controls. Real-time quantitative polymerase chain reaction was used to assess the levels of five GABA-related transcripts in brain regions. We also measured structural and diffusion MRI and cumulative contribution of risk alleles in the GABA pathway genes using polygenic risk scores (PRS) in first-episode treatment-naïve schizophrenic patients (N=117) and age, sex-matched healthy controls (N=86).ResultsErbB4 knockout mice displayed behavioral deficit of PPI, as well as gray and white matter impairment in right sensorimotor cortical-striatal networks. We found significant correlations between gray matter volumes (GMVs) of the somatosensory cortex and PPI as well as GAD1 mRNA expression in controls but not in knockout mice. These findings were confirmed in a human sample where we observed significantly decreased gray and white matter impairment in sensorimotor cortical-striatal networks in schizophrenics. The PRS of GABA-pathway genes also displayed a negative correlation with the GMVs of the somatosensory cortex in patients.DiscussionOur study identified ErbB4 ablation induced prepulse inhibition deficits and GABAergic dysregulation in sensorimotor cortical-lateral striatal networks. We propose that ErbB4 signaling participates in sensorimotor gating dysfunction in schizophrenia by getting involved in somatosensory cortex deficits and GABAergic dysfunction.
Highlights
The current study was to explore how disruption of specific molecular circuits in the cerebral cortex may cause large-scale brain structure deficits and behavior changes via a translational study in conditional Erbb4 mutant mice and patients with schizophrenia
We found significant correlations between gray matter volumes (GMVs) of the somatosensory cortex and prepulse inhibition (PPI) as well as GAD1 mRNA expression in controls but not in knockout mice
These findings were confirmed in a human sample where we observed significantly decreased gray and white matter impairment in sensorimotor cortical-striatal networks in schizophrenics
Summary
A few studies examined the olfactory identification ability in adolescents at-risk for schizophrenia and suggested smell identification deficits as a risk marker for schizophrenia. These studies included adolescents at clinical as well as at genetic risk for schizophrenia. We hypothesize that children at genetic risk for schizophrenia would have the most severe smell identification deficits and that children of bipolar disorder patients would have less severe deficits than the at-risk for schizophrenia group but more severe than the group of children without a psychotic parent. Methods: Participants - The olfactory identification ability was assessed in 202 children of schizophrenia patients (‘children at familial risk for schizophrenia’) in relation to that of 200 children of parents without a psychotic disorder (‘controls’). Chengcheng Zhang*,1, Peiyan Ni2, Tao Li2 1West China Hospital Sichuan University; 2Mental Health Center, West China Hospital of Sichuan University
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