Extra-Synaptic Functions of NRG1 Type I Signaling in Hippocampal γ-Oscillations.
9 affiliations
- 1Department of Neurogenetics, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Lower Saxony, Germany.
- 2Paul Flechsig Institute, Centre for Neuropathology and Brain Research, Medical Faculty, Leipzig University, 04103 Leipzig, Saxony, Germany.
- 3Center for Research in Biotechnology (CIB), Costa Rica Institute of Technology (TEC), 30109 Cartago, Costa Rica.
- 4Department of Neurobiology, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Lower Saxony, Germany.
- 5Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Lower Saxony, Germany.
- 6Neuroscience Research Center (CIN), University of Costa Rica (UCR), 11501-2060 San José, Costa Rica.
- 7Department of Physiology, School of Medicine, University of Costa Rica (UCR), 11501 San José, Costa Rica.
- 8National Center of Biotechnological Innovations (CENIBiot)/National Center of High Technology (CENAT), 1174-1200 San Jose, Costa Rica.
- 9Institute of Anatomy, Leipzig University, 04103 Leipzig, Saxony, Germany.
Abstract
Background and hypothesis
The neurodevelopmental hypothesis of schizophrenia posits that early-acting genetic risk factors precipitate pathological neurodevelopmental processes that result in neural network dysfunctions during adolescence. Human gene variants of the epidermal growth factor-like ligand Neuregulin 1 (NRG1) and its tyrosine kinase receptor ErbB4 are putative risk factors in schizophrenia, and aberrant NRG1 signaling has been implicated in schizophrenia-relevant endophenotypes. However, insight into associated pathomechanisms remains limited.Study design
We modeled embryonic glutamatergic neuron-specific NRG1 type I overexpression in a conditional transgenic mouse line to investigate the impact of early hyperactive NRG1 type I signaling on neuronal network functions in the hippocampus in vivo.Study results
NRG1 type I transgenic mice display abnormal gamma-frequency network oscillations in the adolescent hippocampus, in the absence of neuroinflammation or changes in hippocampal morphology. Instead, we found extra-synaptic NRG1 type I accumulation, which was associated with ErbB4 hyperphosphorylation, an increased size and number of Kv2.1 potassium channel-marked endoplasmic reticulum (ER)-plasma membrane (PM) junctions, and a reduction of A-type potassium channel currents in pyramidal cells.Conclusions
Together, these findings suggest a model in which early-onset extra-synaptic NRG1 type I accumulation at ER-PM junctions causes sustained changes in neuronal excitability, ultimately contributing to deficits in neuronal network oscillations as observed in various neuropsychiatric disorders.
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BibTeX
@article{sotobernardini2026extrasynaptic,
title = {{Extra-Synaptic Functions of NRG1 Type I Signaling in Hippocampal γ-Oscillations.}},
author = {María Clara Soto-Bernardini and Sua Jeong and Hadiseh Hosseinnia and Bekir Altas and Hong Jun Rhee and Chungku Lee and Yvonne Schill and Ulrike Zeitschel and Tilmann Götze and Julia Hellriegel and Maria Lehning and Oscar Brenes and Jaime Fornaguera and José Aníbal Mora-Villalobos and Robert Fledrich and Ruth M Stassart and Jeong Seop Rhee and Markus H Schwab},
journal = {Schizophrenia bulletin},
year = {2026},
month = oct,
doi = {10.1093/schbul/sbag168},
url = {https://europepmc.org/article/MED/42960987},
note = {CC BY},
}
RIS
TY - JOUR
TI - Extra-Synaptic Functions of NRG1 Type I Signaling in Hippocampal γ-Oscillations.
AU - María Clara Soto-Bernardini
AU - Sua Jeong
AU - Hadiseh Hosseinnia
AU - Bekir Altas
AU - Hong Jun Rhee
AU - Chungku Lee
AU - Yvonne Schill
AU - Ulrike Zeitschel
AU - Tilmann Götze
AU - Julia Hellriegel
AU - Maria Lehning
AU - Oscar Brenes
AU - Jaime Fornaguera
AU - José Aníbal Mora-Villalobos
AU - Robert Fledrich
AU - Ruth M Stassart
AU - Jeong Seop Rhee
AU - Markus H Schwab
PY - 2026
DA - 2026/10/01
JO - Schizophrenia bulletin
DO - 10.1093/schbul/sbag168
UR - https://europepmc.org/article/MED/42960987
AB - Background and hypothesis The neurodevelopmental hypothesis of schizophrenia posits that early-acting genetic risk factors precipitate pathological neurodevelopmental processes that result in neural network dysfunctions during adolescence. Human gene variants of the epidermal growth factor-like ligand Neuregulin 1 (NRG1) and its tyrosine kinase receptor ErbB4 are putative risk factors in schizophrenia, and aberrant NRG1 signaling has been implicated in schizophrenia-relevant endophenotypes. However, insight into associated pathomechanisms remains limited.Study design We modeled embryonic glutamatergic neuron-specific NRG1 type I overexpression in a conditional transgenic mouse line to investigate the impact of early hyperactive NRG1 type I signaling on neuronal network functions in the hippocampus in vivo.Study results NRG1 type I transgenic mice display abnormal gamma-frequency network oscillations in the adolescent hippocampus, in the absence of neuroinflammation or changes in hippocampal morphology. Instead, we found extra-synaptic NRG1 type I accumulation, which was associated with ErbB4 hyperphosphorylation, an increased size and number of Kv2.1 potassium channel-marked endoplasmic reticulum (ER)-plasma membrane (PM) junctions, and a reduction of A-type potassium channel currents in pyramidal cells.Conclusions Together, these findings suggest a model in which early-onset extra-synaptic NRG1 type I accumulation at ER-PM junctions causes sustained changes in neuronal excitability, ultimately contributing to deficits in neuronal network oscillations as observed in various neuropsychiatric disorders.
SN - 1787-9965
SN - 1745-1701
SN - 0586-7614
ER -