Extra-Synaptic Functions of NRG1 Type I Signaling in Hippocampal γ-Oscillations
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Published on: August 14, 2015
María Clara Soto-Bernardini1,2,3, Sua Jeong4, Hadiseh Hosseinnia2
1Department of Neurogenetics, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Lower Saxony, Germany.
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.
