ABSTRACT
The neuregulin 1 (NRG1) ErbB4 module is at the core of an "at risk" signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of "brain-wide" vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.
Subject(s)
Brain , Endophenotypes , Glutamic Acid/metabolism , Nerve Net , Neuregulin-1/metabolism , Psychomotor Agitation , Receptor, ErbB-4/metabolism , Schizophrenia , Animals , Behavior, Animal/physiology , Brain/metabolism , Brain/physiopathology , Disease Models, Animal , Embryo, Mammalian , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Net/metabolism , Nerve Net/physiopathology , Psychomotor Agitation/metabolism , Psychomotor Agitation/physiopathology , Schizophrenia/metabolism , Schizophrenia/physiopathology , Signal Transduction/physiologyABSTRACT
In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells induce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental.
Subject(s)
Demyelinating Diseases/genetics , Neuregulin-1/genetics , Paracrine Communication , Schwann Cells/metabolism , Sural Nerve/metabolism , Animals , Animals, Genetically Modified , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/metabolism , Charcot-Marie-Tooth Disease/pathology , Demyelinating Diseases/metabolism , Demyelinating Diseases/pathology , Diabetes Mellitus, Type 1/complications , Diabetic Neuropathies/etiology , Diabetic Neuropathies/genetics , Diabetic Neuropathies/metabolism , Diabetic Neuropathies/pathology , Humans , MAP Kinase Signaling System , Mice , Mice, Transgenic , Microscopy, Electron , Motor Activity , Myelin Proteins/genetics , Neuregulin-1/metabolism , Neuritis, Autoimmune, Experimental/genetics , Neuritis, Autoimmune, Experimental/metabolism , Neuritis, Autoimmune, Experimental/pathology , Neuroglia/metabolism , Rats , Receptor, ErbB-2/metabolism , Schwann Cells/ultrastructure , Sciatic Nerve/injuries , Signal Transduction , Sural Nerve/ultrastructure , Tibial NerveABSTRACT
Michael W. Sereda was incorrectly associated with the Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany. The correct affiliations for Michael W. Sereda are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany and Department of Clinical Neurophysiology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
ABSTRACT
The cerebellar cortex is involved in the control of diverse motor and non-motor functions. Its principal circuit elements are the Purkinje cells that integrate incoming excitatory and local inhibitory inputs and provide the sole output of the cerebellar cortex. However, the transcriptional control of circuit assembly in the cerebellar cortex is not well understood. Here, we show that NeuroD2, a neuronal basic helix-loop-helix (bHLH) transcription factor, promotes the postnatal survival of both granule cells and molecular layer interneurons (basket and stellate cells). However, while NeuroD2 is not essential for the integration of surviving granule cells into the excitatory circuit, it is required for the terminal differentiation of basket cells. Axons of surviving NeuroD2-deficient basket cells follow irregular trajectories and their inhibitory terminals are virtually absent from Purkinje cells in Neurod2 mutants. As a result inhibitory, but not excitatory, input to Purkinje cells is strongly reduced in the absence of NeuroD2. Together, we conclude that NeuroD2 is necessary to instruct a terminal differentiation program in basket cells that regulates targeted axon growth and inhibitory synapse formation. An imbalance of excitation and inhibition in the cerebellar cortex affecting Purkinje cell output may underlay impaired adaptive motor learning observed in Neurod2 mutants.
