L'Interaction entre un gène de risque de trouble mental et un changement de polarité de développement de l'action GABA conduit à un déséquilibre excitation-inhibition

Aperçu: G.M.

Le déséquilibre excitation-inhibition (E-I) est considéré comme une caractéristique de divers troubles du développement neurologique, notamment la schizophrénie et l'autisme. 

La manière dont les facteurs de risque génétiques perturbent la formation coordonnée des synapses glutamatergique et GABAergique pour provoquer un déséquilibre E-I n'est pas bien comprise. 

Ici, nous montrons que l'inactivation de Disrupted-in-schizophrenia 1 (DISC1), un gène de risque de troubles mentaux majeurs, conduit à un déséquilibre E-I dans les neurones à granules dentés matures. Nous avons constaté que des apports excessifs en GABAergique d'interneurones exprimant la parvalbumine, mais non la somatostatine, favorisent la formation de synapses glutamatergique et gABAergique dans des neurones immatures mutants. Suite au passage de la polarité de signalisation GABAergique de dépolarisation à hyperpolarisation au cours de la maturation neuronale, une inhibition accrue des entrées excessives parvalbumine + GABAergique entraîne une perte des synapses glutamatergiques excitatrices dans les neurones mutants matures, entraînant un déséquilibre E-I. 

Nos résultats fournissent des informations sur le rôle de dépolarisation du GABA dans le développement de la balance E-I et sur la manière dont il peut être influencé par les facteurs de risque génétiques des troubles mentaux.

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

Kang E¹, Song J², Lin Y³, Park J⁴, Lee JH⁴, Hussani Q⁴, Gu Y⁵, Ge S⁵, Li W⁶, Hsu KS³, Berninger B⁷, Christian KM⁸, Song H⁹, Ming GL¹⁰.

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.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 31390557

DOI: 10.1016/j.celrep.2019.07.024