Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders

Authors

  • Peter Penzes,

    Corresponding author
    1. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
    • Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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    • These authors contributed equally to this work
  • Andres Buonanno,

    1. Section on Molecular Neurobiology, Eunice Shriver Kennedy NICHD, National Institutes of Health, Program of Developmental Neurobiology, Bethesda, Maryland, USA
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    • These authors contributed equally to this work
  • Maria Passafaro,

    1. CNR Institute of Neuroscience and Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
    2. Dulbecco Telethon Institute, CNR, Institute of Neuroscience, Milan, Italy
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    • These authors contributed equally to this work
  • Carlo Sala,

    1. CNR Institute of Neuroscience and Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
    2. Neuromuscular Diseases and Neuroimmunology, Neurological Institute and Foundation ‘Carlo Besta’, Milan, Italy
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    • These authors contributed equally to this work
  • Robert A. Sweet

    1. Department of Psychiatry, University of Pittsburgh School of Medicine, Biomedical Science Tower, Pittsburgh, Pennsylvania, USA
    2. VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Biomedical Science Tower, Pittsburgh, Pennsylvania, USA
    3. Department of Neurology, University of Pittsburgh School of Medicine, Biomedical Science Tower, Pittsburgh, Pennsylvania, USA
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    • These authors contributed equally to this work

Address correspondence and reprint requests to Peter Penzes, Department of Physiology, Northwestern University Feinberg School of Medicine, 303 E, Chicago Avenue, Chicago, IL 60611, USA. E-mail: p-penzes@northwestern.edu

Abstract

Psychiatric and neurodegenerative disorders, including intellectual disability, autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease, pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorders. Multiple lines of evidence implicate excitatory and inhibitory synaptic circuits in the cortex and hippocampus as key cellular substrates of pathogenesis in these disorders. Excitatory/inhibitory balance – modulated largely by dopamine – critically regulates cortical network function, neural network activity (i.e. gamma oscillations) and behaviors associated with psychiatric disorders. Understanding the molecular underpinnings of synaptic pathology and neuronal network activity may thus provide essential insight into the pathogenesis of these disorders and can reveal novel drug targets to treat them. Here, we discuss recent genetic, neuropathological, and molecular studies that implicate alterations in excitatory and inhibitory synaptic circuits in the pathogenesis of psychiatric disorders across the lifespan.

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