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Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.
Yilmaz, Melis; Yalcin, Esra; Presumey, Jessy; Aw, Ernest; Ma, Minghe; Whelan, Christopher W; Stevens, Beth; McCarroll, Steven A; Carroll, Michael C.
Affiliation
  • Yilmaz M; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Yalcin E; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Presumey J; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Aw E; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Ma M; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Whelan CW; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Stevens B; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • McCarroll SA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Carroll MC; Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Neurosci ; 24(2): 214-224, 2021 02.
Article in En | MEDLINE | ID: mdl-33353966
The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Schizophrenic Psychology / Synapses / Behavior, Animal / Complement C4 Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nat Neurosci Journal subject: NEUROLOGIA Year: 2021 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Schizophrenia / Schizophrenic Psychology / Synapses / Behavior, Animal / Complement C4 Type of study: Prognostic_studies Limits: Animals Language: En Journal: Nat Neurosci Journal subject: NEUROLOGIA Year: 2021 Document type: Article Affiliation country: Estados Unidos Country of publication: Estados Unidos