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

Cell Reports
Eunchai KangGuo-li Ming

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.

Citations

Nov 26, 2019·Rejuvenation Research·James Larrick, Andrew R Mendelsohn
Feb 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Saori YokoiHideaki Takeuchi
Jan 14, 2021·Translational Psychiatry·Emily T WoodShulamite A Green
Apr 20, 2021·Current Opinion in Neurobiology·Mariela F TrincheroAlejandro F Schinder

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