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A Critical Perspective on the Synaptic Pruning Hypothesis of Schizophrenia Pathogenesis

  • Matthew B. Johnson
    Affiliations
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts

    Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, Massachusetts
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  • Steven E. Hyman
    Correspondence
    Address correspondence to Steven E. Hyman, M.D.
    Affiliations
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts
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      Schizophrenia characteristically begins during adolescence—like many psychiatric disorders (
      • Dalsgaard S.
      • Thorsteinsson E.
      • Trabjerg B.B.
      • Schullehner J.
      • Plana-Ripoll O.
      • Brikell I.
      • et al.
      Incidence rates and cumulative incidences of the full spectrum of diagnosed mental disorders in childhood and adolescence.
      )—starting with cognitive impairments and deficit symptoms followed by psychosis. Schizophrenia is highly heterogeneous in onset, symptom severity, mood disturbances, comorbidities, treatment response, and outcomes. It is also highly polygenic, which likely precludes a unitary pathophysiologic process because loading of risk alleles and relevant environmental exposures represents a complex stochastic grab bag. There are not, however, an infinite number of processes that could produce adolescent onset of unremitting cognitive and deficit symptoms followed by relapsing and remitting psychosis. In short, diverse affected pathways likely converge on a smaller number of basic mechanisms. Based on the evidence to date, arguably a leading candidate mechanism is the synaptic pruning hypothesis.
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