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.
Bibliographical noteAcknowledgments: 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.
- circuit development
- depolarizing GABA
- excitation/inhibition imbalance
- GABA polarity switch
- GABA signaling
- mental disorder
- Parvalbumin interneuron
- synapse formation