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.

Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls

“…It has been shown that NRG1 can enhance neuron dendrite complexity, which could be blocked by a knockdown of DISC1 . Furthermore, DISC1 expression can be increased by NRG1 [24]. Consistent with the findings in NRG1 , its co-worker DISC1 also seems not to be manipulated by THC.…”

“…DISC1 is an intracellular protein which has been described as a cofactor in dendrite growth [24]. Although knowledge about its detailed function remains diffuse in some areas, DISC1 translocation has been proven in a Scottish family with a high number of schizophrenic individuals [25, 26].…”

DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

“…Altered expression was also confirmed for genes encoding the historical candidate NRG1 26 and its receptor ERBB4 (Fig. 2e ), both of which have previously been linked functionally to DISC1 27 , 28 . Expression of 12 of 52 genes encoding synaptic proteins that are targeted by recurrent CNVs in schizophrenia 3 is also altered (hypergeometric probability p = 0.001, Supplementary Table 1a, b ).…”

Sex-specific deficits in neurite density and white matter integrity are associated with targeted disruption of exon 2 of the Disc1 gene in the rat

“…A salient example of the added utility of using NODDI is demonstrated in Colgan et al, where a tau pathology murine model demonstrated significantly higher neurite density in neocortex than in wild-type controls, correlating with the degree of tau burden, in the absence of significant FA and MD findings 51 . As DISC1 serves to regulate the development of synaptic growth and the organization of trans-synaptic structures and functions, it would thus be predicted to impact neuroimaging measures of neurite density and orientation 44,45,52–54 . As anticipated, our Disc1 svΔ2 model harbors decreased neurite density in numerous salient regions of the brain including the hippocampal formation, the basal ganglia, and the neocortex, consistent with previous studies of both dysmorphic and decreased dendritic density and arborization as seen in models of both Disc1 under- and overexpression 55,56 .…”