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

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

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	1419-1428.e3
Number of pages	14
Journal	Cell Reports
Volume	28
Issue number	6
Early online date	6 Aug 2019
DOIs	https://doi.org/10.1016/j.celrep.2019.07.024
Publication status	Published - 6 Aug 2019
Externally published	Yes

Bibliographical note

Acknowledgments: We thank members of the Ming and Song laboratories for comments and suggestions, D. Johnson for technical support, and J. Schnoll for lab coordination.
This work was supported by grants from the National Institutes of Health (NIH) (R01MH105128 and R35NS097370 to G.-L.M. and R37NS047344 to H.S.) and from the National Alliance for Research on Schizophrenia and Depression (NARSAD) to G.-L.M., H.S., and E.K.

Author Contributions: E.K. and J.S contributed equally to this work. J.S. performed electrophysiological analysis and E.K. performed morphological analysis. Y.L. and K.-S.H. contributed to electrophysiology data collection, Y.G. and S.G. helped with some of the retrovirus production, and B.B. helped with rabies synaptic tracing. J.P., J.H.L., Q.H., W.L., and K.M.C. contributed to additional data collection. E.K., J.S., H.S., and G-L.M. designed the project and wrote the manuscript.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kang_et_al_CellRep_Interplay_between_a_mental_VOR
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Cite this

Kang, E., Song, J., Lin, Y., Park, J., Lee, J. H., Hussani, Q., Gu, Y., Ge, S., Li, W., Hsu, K., Berninger, B., Christian, K. M., Song, H., & Ming, G. (2019). Interplay between a Mental Disorder Risk Gene and Developmental Polarity Switch of GABA Action Leads to Excitation-Inhibition Imbalance. Cell Reports, 28(6), 1419-1428.e3. https://doi.org/10.1016/j.celrep.2019.07.024

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

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

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AU - Song, Juan

AU - Lin, Yuting

AU - Park, Jaesuk

AU - Lee, Jennifer H.

AU - Hussani, Qassim

AU - Gu, Yan

AU - Ge, Shaoyu

AU - Li, Weidong

AU - Hsu, Kuei-sen

AU - Berninger, Benedikt

AU - Christian, Kimberly M.

AU - Song, Hongjun

AU - Ming, Guo-li

N1 - Acknowledgments: We thank members of the Ming and Song laboratories for comments and suggestions, D. Johnson for technical support, and J. Schnoll for lab coordination. This work was supported by grants from the National Institutes of Health (NIH) (R01MH105128 and R35NS097370 to G.-L.M. and R37NS047344 to H.S.) and from the National Alliance for Research on Schizophrenia and Depression (NARSAD) to G.-L.M., H.S., and E.K. Author Contributions: E.K. and J.S contributed equally to this work. J.S. performed electrophysiological analysis and E.K. performed morphological analysis. Y.L. and K.-S.H. contributed to electrophysiology data collection, Y.G. and S.G. helped with some of the retrovirus production, and B.B. helped with rabies synaptic tracing. J.P., J.H.L., Q.H., W.L., and K.M.C. contributed to additional data collection. E.K., J.S., H.S., and G-L.M. designed the project and wrote the manuscript.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

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Eunchai Kang

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

Abstract

Bibliographical note

Keywords

UN SDGs

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Fingerprint

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Eunchai Kang

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