Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex

Seshadri, S., Faust, T., Ishizuka, K., Delevich, K., Chung, Y., Kim, S. H., Cowles, M., Niwa, M., Jaaro-Peled, H., Tomoda, T., Lai, C., Anton, E. S., Li, B., Sawa, A. (December 2015) Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nat Commun, 6. p. 10118. ISSN 2041-1723

Abstract

Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By cell type-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likely mediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit. Post-mortem brain analyses and some genetic studies have reported interneuronal deficits and involvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest a mechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to these deficits.

Item Type: Paper
CSHL Authors:
Communities: CSHL labs > Li lab
School of Biological Sciences > Publications
Depositing User: Matthew Dunn
Date: 11 December 2015
Date Deposited: 14 Dec 2020 18:04
Last Modified: 01 Mar 2024 14:49
PMCID: PMC4682104
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39639

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