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Cell Rep. 2019 Aug 6;28(6):1419-1428.e3. doi: 10.1016/j.celrep.2019.07.024.

Interplay between a Mental Disorder Risk Gene and Developmental Polarity Switch of GABA Action Leads to Excitation-Inhibition Imbalance.

Author information

1
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan.
4
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
6
Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
7
Center for Developmental Neurobiology, King's College London, London SE1UL, UK.
8
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
10
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: gming@pennmedicine.upenn.edu.

Abstract

Excitation-inhibition (E-I) imbalance is considered a hallmark of various neurodevelopmental disorders, including schizophrenia and autism. How genetic risk factors disrupt coordinated glutamatergic and GABAergic synapse formation to cause an E-I imbalance is not well understood. Here, we show that knockdown of Disrupted-in-schizophrenia 1 (DISC1), a risk gene for major mental disorders, leads to E-I imbalance in mature dentate granule neurons. We found that excessive GABAergic inputs from parvalbumin-, but not somatostatin-, expressing interneurons enhance the formation of both glutamatergic and GABAergic synapses in immature mutant neurons. Following the switch in GABAergic signaling polarity from depolarizing to hyperpolarizing during neuronal maturation, heightened inhibition from excessive parvalbumin+ GABAergic inputs causes loss of excitatory glutamatergic synapses in mature mutant neurons, resulting in an E-I imbalance. Our findings provide insights into the developmental role of depolarizing GABA in establishing E-I balance and how it can be influenced by genetic risk factors for mental disorders.

KEYWORDS:

DISC1; GABA polarity switch; GABA signaling; Parvalbumin interneuron; circuit development; depolarizing GABA; excitation/inhibition imbalance; homeostasis; mental disorder; synapse formation

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