Neuregulin Signaling in Neuropsychiatric Disorders

Neuregulins are a family of epidermal growth factor-like ligands that engage ErbB receptor tyrosine kinases to orchestrate neuronal development, synaptic modulation and plasticity in the mature brain. Signalling through ErbB4 and related subunits regulates the balance between excitation and inhibition by refining GABAergic interneuron function, promoting dendritic arborisation in pyramidal cells and influencing neurotransmitter release. Disruption of neuregulin–ErbB pathways is implicated in the aetiology of schizophrenia, bipolar disorder and depression, with genetic variation in NRG1 and NRG3 linked to cognitive deficits, altered sensorimotor gating and mood dysregulation. Proteolytic cleavage of neuregulin precursors, activation of downstream kinases such as PI3K and MAPK, and cross-talk with glutamatergic NMDA receptors underlie dynamic homeostatic adjustments within cortical microcircuits. Translational studies further suggest that modulation of neuregulin signalling may restore cortical plasticity in adulthood and inform the development of targeted therapeutics for neuropsychiatric conditions.

Research from Nature Portfolio

Recent studies have uncovered an intimate bidirectional relationship between neuregulin-2 and NMDA receptors in cortical interneurons. Pro-NRG2 accumulates at subsurface cisternae and is rapidly cleaved upon NMDA receptor activation, releasing an extracellular domain that enhances association of ErbB4 with GluN2B-containing NMDA receptors. This feedback mechanism selectively downregulates NMDA currents in ErbB4-positive interneurons, thereby fine-tuning inhibitory tone and synchronisation within cortical networks. Such findings illuminate a molecular basis for neuregulin-mediated control of excitatory–inhibitory balance and offer insights into cognitive dysfunctions characteristic of psychiatric disorders.

Neuregulin Signaling in Neuropsychiatric Disorders publication trend

The graph below shows the total number of articles in neuregulin signaling in neuropsychiatric disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Neuregulin: A family of extracellular ligands that activate ErbB receptor tyrosine kinases to regulate neural development, synapse formation and plasticity.

ErbB4: A receptor tyrosine kinase for neuregulins, highly expressed in GABAergic interneurons and critical for inhibitory circuit modulation.

GABAergic interneuron: An inhibitory neuron that releases γ-aminobutyric acid (GABA) to regulate excitatory activity and network synchrony.

NMDA receptor: A subtype of glutamate-gated ion channel involved in synaptic plasticity, learning and memory.

Proteolytic shedding: Enzymatic cleavage of membrane-bound precursors to release active extracellular domains.

Endoplasmic reticulum–plasma membrane (ER–PM) junction: Specialized contact sites that organise signalling molecules and regulate calcium and lipid exchange.

Phosphoinositide 3-kinase (PI3K): A lipid kinase that transduces receptor signals to intracellular pathways governing growth, survival and synaptic function.

References

1. ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms*. Journal of Biological Chemistry (2008).
2. A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling. Nature Communications (2015).
3. nNOS in Erbb4-positive neurons regulates GABAergic transmission in mouse hippocampus. Cell Death & Disease (2024).
4. Genetic labeling reveals spatial and cellular expression pattern of neuregulin 1 in mouse brain. Cell & Bioscience (2023).
5. ER-PM Junctions on GABAergic Interneurons Are Organized by Neuregulin 2/VAP Interactions and Regulated by NMDA Receptors. International Journal of Molecular Sciences (2023).