Summary: Researchers report that neuregulin 3, a protein found at elevated levels in people with schizophrenia, suppresses the assembly of a protein complex essential for efficient neural communication, impairing glutamate release.
Source: Case Western Reserve.
An international team identifies how neuregulin 3 disrupts glutamate signaling in schizophrenia
Researchers led by scientists at Case Western Reserve University School of Medicine have uncovered a previously unknown mechanism by which neuregulin 3 (NRG3), a protein elevated in several severe mental illnesses, controls neurotransmitter release. Their work reveals that increased NRG3 levels interfere with the presynaptic machinery needed for glutamate transmission, offering new insight into schizophrenia’s cellular basis and suggesting possible therapeutic directions.
Published in Proceedings of the National Academy of Sciences, the study combined genetic, electrophysiological, biochemical, and molecular approaches to define the role of NRG3 in neuronal communication. The collaborative team included investigators from Case Western Reserve University School of Medicine, Louis Stokes Cleveland Veterans Affairs Medical Center, Augusta University, Nanchang University, and Guangzhou Medical University.
Certain variants in the NRG3 gene are associated with higher risk for schizophrenia and other severe psychiatric disorders. Until now, how elevated NRG3 contributes to disease biology was unclear. “We have identified a novel function of a schizophrenia susceptibility gene, neuregulin 3, which provides insight into cellular mechanisms of this devastating disorder and could lead to new therapeutic targets,” said Lin Mei, PhD, professor and chair of the Department of Neurosciences at Case Western Reserve University School of Medicine and the study’s senior author. Understanding how NRG3 alters synaptic function could guide development of drugs that restore normal signaling in affected circuits.
Schizophrenia affects nearly 1 in 100 American adults and remains poorly understood. The disorder arises from complex interactions among many proteins and neurotransmitters, which makes isolating causative mechanisms difficult. The present study identifies a specific, previously unrecognized pathway involving NRG3 and presynaptic regulation of glutamate release.
To pinpoint NRG3’s role in behavior and synaptic physiology, the team engineered mice with targeted mutations in the Nrg3 gene limited to particular neuronal populations. When Nrg3 was knocked out in pyramidal neurons—cortical cells that drive network activation—the mutant mice developed behavioral traits consistent with schizophrenia-related deficits. These animals showed normal hearing and reflexes but exhibited hyperactivity, impaired spatial memory and maze navigation, and reduced social approach toward unfamiliar mice. These behavioral changes support a role for NRG3 in disease-relevant neuronal populations and help identify which cell types are most affected.
At the cellular level, analyses of brain tissue and cultured neurons showed that NRG3 acts presynaptically to inhibit assembly of the SNARE complex, a multimeric protein assembly required for vesicle fusion and neurotransmitter release. Proper SNARE complex formation is critical for release of glutamate, the primary excitatory neurotransmitter that underlies neuronal activation and learning. The researchers found that loss of Nrg3 in pyramidal neurons increased glutamatergic transmission without altering inhibitory GABAergic signaling, indicating a cell-autonomous effect on excitatory synapses.
Conversely, elevating NRG3 to levels comparable to those seen in patients suppressed glutamate release. In cultured neurons, higher NRG3 impaired SNARE complex formation and reduced the probability of glutamate release, producing a state of glutamatergic hypofunction. Because glutamate dysregulation is implicated in cognitive and perceptual symptoms of schizophrenia, these findings provide a plausible molecular link between elevated NRG3 and the disease’s functional deficits.
Importantly, NRG3’s mode of action differs from other neuregulin family members. For example, neuregulin 1 primarily influences different signaling pathways and acts through ErbB4 receptors on interneurons. The Case Western Reserve team found that NRG3’s inhibition of glutamate release does not require ErbB4 activation, indicating a distinct presynaptic mechanism unique to NRG3.
These results nominate NRG3 as a potential therapeutic target. Drugs that normalize NRG3 levels or counteract its suppression of SNARE complex assembly could restore glutamate signaling in affected neurons, representing a novel strategy for treating schizophrenia and related psychiatric conditions. “Identifying a novel mechanism of action is a prerequisite to understanding a disorder, and to development of therapeutic interventions,” Mei said. “Of course, the road could be long to get there, but we are on our way.”
Funding: This research was supported in part by grants from the National Institutes of Health (MH083317, MH109280, NS082007, and NS090083 to L.M.; and AG051773 and AG045781 to W.-C. X.).
Source: Ansley Gogol – Case Western Reserve University School of Medicine.
Publisher: Organized by Neuroscience News.
Image Source: Image is in the public domain.
Original Research: Abstract published in PNAS (Proceedings of the National Academy of Sciences).
DOI: 10.1073/pnas.1716322115
Case Western Reserve (2018, February 21). Novel Mechanism Behind Schizophrenia Uncovered. Neuroscience News. Retrieved February 21, 2018.
Abstract
Controlling glutamate release by neuregulin 3 via inhibition of SNARE-complex assembly
Neuregulin 3 (NRG3) is a growth factor and a genetic risk factor for severe mental illnesses such as schizophrenia, bipolar disorder, and major depression, but its physiological function has been incompletely understood. The study shows that loss of Nrg3 in GFAP-Nrg3f/f mice increased glutamatergic transmission while leaving GABAergic transmission unchanged. Similar phenotypes were found in Nex-Nrg3f/f mice with Nrg3 deleted specifically in pyramidal neurons, indicating a cell-autonomous regulation of excitatory signaling. Mice lacking Nrg3 in pyramidal neurons exhibited behavioral deficits relevant to mental illness. Electrophysiological assays revealed decreased paired-pulse facilitation, faster decay of NMDAR currents in MK801 treatment, and increased minimal stimulation responses, all consistent with increased glutamate release probability after Nrg3 loss. Mechanistically, Nrg3 functions as a presynaptic regulator of SNARE-complex assembly, and increased NRG3 levels—as observed in patients—suppressed glutamatergic transmission. Together, these findings demonstrate that NRG3 controls glutamate release by modulating SNARE assembly at presynaptic terminals, a mechanism distinct from NRG1’s ErbB4-mediated effects, and provide a pathophysiological explanation for glutamatergic hypofunction in NRG3-associated psychiatric disease.