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

Research output: Contribution to journalArticle

Eunchai Kang, Juan Song, Yuting Lin, Jaesuk Park, Jennifer H. Lee, Qassim Hussani, Yan Gu, Shaoyu Ge, Weidong Li, Kuei sen Hsu, Benedikt Berninger, Kimberly M. Christian, Hongjun Song, Guo li Ming

Original languageEnglish
Pages (from-to)1419-1428.e3
JournalCell Reports
Volume28
Issue number6
DOIs
Publication statusPublished - 6 Aug 2019

Documents

  • S2211-1247(19)30921-0

    S2211_1247_19_30921_0.pdf, 2 MB, application/pdf

    9/08/2019

    Final published version

    CC BY-NC-ND

King's Authors

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. Kang et al. uncover a circuit-level homeostatic mechanism coordinating glutamatergic and GABAergic synapse formation during neuronal maturation and reveal how excitation-inhibition imbalance develops due to a genetic insult.

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