Neuregulin-1 Regulates Cortical Inhibitory Neuron Dendrite and Synapse Growth through DISC1.

Brianna K Unda,Vickie Kwan,Karun K Singh

doi:10.1155/2016/7694385

Brianna K Unda, Vickie Kwan + Show 1 more

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https://doi.org/10.1155/2016/7694385

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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.

Highlights

Proper functioning of the central nervous system requires a fine balance between excitatory and inhibitory neurotransmission [1]
We determined that NRG1 treatment for two days led to an increase in dendritic morphology, which was abolished when Disrupted in Schizophrenia 1 (DISC1) expression was decreased using shRNA (Supplementary Figures 1D–F). These results suggest that NRG1 regulates the dendritic and synaptic growth of cortical inhibitory neurons and requires DISC1 expression to mediates these effects
We found a significant increase in doublepositive DISC1/vesicular glutamate transporter 1 (VGLUT1) puncta on the cell body and primary dendrites on cortical inhibitory neurons (Figures 1(b), 1(e), and 1(h))

Summary

Introduction

Proper functioning of the central nervous system requires a fine balance between excitatory and inhibitory neurotransmission [1]. Understanding the molecular pathways that regulate inhibitory neuron development may shed light on how their function is disrupted in these disorders. In this regard, the morphological development of cortical inhibitory neurons is governed by both extracellular (e.g., neuronal activity [14] and NRG1 [15,16,17]) and intracellular signalling molecules (e.g., the distal-less homeobox (Dlx) family of transcription factors [18]), which regulate the branching of dendrites and formation of synapses. The underlying signalling pathways governing inhibitory neuron development and, how these processes may be affected in neurodevelopmental disorders are still poorly understood

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