title: Neuregulin-1 Regulates Cortical Inhibitory Neuron Dendrite and Synapse Growth through DISC1.
abstract: Cortical inhibitory neurons play crucial roles in regulating excitatory synaptic networks and cognitive function and aberrant development of these cells have been linked to neurodevelopmental disorders. The secreted neurotrophic factor Neuregulin-1 (NRG1) and its receptor ErbB4 are established regulators of inhibitory neuron connectivity, but the developmental signalling mechanisms regulating this process remain poorly understood. Here, we provide evidence that NRG1-ErbB4 signalling functions through the multifunctional scaffold protein, Disrupted in Schizophrenia 1 (DISC1), to regulate the development of cortical inhibitory interneuron dendrite and synaptic growth. We found that NRG1 increases inhibitory neuron dendrite complexity and glutamatergic synapse formation onto inhibitory neurons and that this effect is blocked by expression of a dominant negative DISC1 mutant, or DISC1 knockdown. We also discovered that NRG1 treatment increases DISC1 expression and its localization to glutamatergic synapses being made onto cortical inhibitory neurons. Mechanistically, we determined that DISC1 binds ErbB4 within cortical inhibitory neurons. Collectively, these data suggest that a NRG1-ErbB4-DISC1 signalling pathway regulates the development of cortical inhibitory neuron dendrite and synaptic growth. Given that NRG1, ErbB4, and DISC1 are schizophrenia-linked genes, these findings shed light on how independent risk factors may signal in a common developmental pathway that contributes to neural connectivity defects and disease pathogenesis.
authors.affiliation: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada L8S 4K1; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8S 4K1.
authors.forename: Brianna K
authors.identifier: 0000-0003-4926-1052
authors.initials: BK
authors.lastname: Unda
authors.affiliation: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada L8S 4K1; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8S 4K1.
authors.forename: Vickie
authors.initials: V
authors.lastname: Kwan
authors.affiliation: Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada L8S 4K1; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada L8S 4K1.
authors.forename: Karun K
authors.identifier: 0000-0001-8301-3533
authors.initials: KK
authors.lastname: Singh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D020890:Neuregulin-1 / Q000494:pharmacology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: C498794:Disc1 protein, mouse; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1