The central nervous system component of peripheral neuropathies: a crucial liaison between microglia and motor neurons?
Developmental Neurobiology
Final Report Abstract
Inherited peripheral neuropathies are a group of genetic disorders that primarily affect peripheral nerves. The most common disorder is CMT1A (Charcot-Marie-Tooth disease type 1A). Patients suffer from slowly progressing muscle weakness and sensory deficits. In CMT1A, a genetic duplication in the chromosomal region 17p12 leads to an overproduction of the peripheral myelin protein 22 (PMP22). This predominantly affects Schwann cells, the myelinating glial cells of the peripheral nervous system, and leads to impaired production and maintenance of myelin. In this study, we aimed to investigate if a specific genetic defect in Schwann cells can have consequences beyond the nerve. Specifically, we examined the interface between central nervous system (CNS) afferents and spinal cord motor neurons, whose axons extend to peripheral nerves. Previous studies of acute nerve injury models demonstrate that damage to the peripheral nerve can lead to a loss of synapses onto motor neurons and a local response by microglial cells, the immune cells of the CNS. If similar changes occur in the context of chronic neuropathy with slowly progressing damage to the peripheral nerve is so far unexplored but could present a highly relevant pathomechanism for motor neuron dysfunction observed during early stages of CMT1A. To evaluate different disease stages, we employed a transgenic mouse model of CMT1A (PMP22 tg mouse) and performed a comprehensive molecular and immunohistochemical analysis of developmental, adult and aged time points. We identified a specific microglia response starting at postnatal stages which indicated increased monitoring of the motor neuron soma. Notably, microglia in PMP22 tg mice preferentially contacted a specific type of synapse called the C-bouton. These large cholinergic synapses are located at the motor neuron soma and proximal dendrites and control the responsiveness of a motor neuron, so called the motor neuron excitability. Alterations in C-boutons have been observed in several motor neuron diseases, such as amyotrophic lateral sclerosis. Thus, we addressed whether increased microglial monitoring was linked to altered C-bouton structure and function. We found that C-boutons are enlarged starting at postnatal stages. In addition, we detected a reduced number of C-boutons at 6 months, suggesting that abnormal formation of C-boutons can result in their loss from motor neurons at later stages. Interestingly, the enlargement of C-bouton synapses coincided with an overaccumulation of the signalling protein Neuregulin-1 (NRG1) in the postsynaptic compartment of the C-bouton. Consistent with this finding, using motor neuron-specific NRG1 mouse mutants, we demonstrated that NRG1 is necessary for the proper maturation of C-boutons. In ongoing studies, we are examining whether NRG1 accumulation at C-boutons might provide an activating signal for microglia recruitment. Using mutant mice that specifically lack the NRG1 receptor ERBB2/4 in microglia, we will explore whether microglia sense elevated NRG1 signals from affected motor neurons in CMT1A. Together, our findings suggest a working model where chronic peripheral nerve damage propagates to the connected motor circuit and triggers abnormal C-bouton development and microglial reactivity. It is essential to elucidate such circuit-level effects that contribute to disease pathogenesis for a complete understanding of the disease.
Publications
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Schwann cell functions in peripheral nerve development and repair. Neurobiology of Disease, 176, 105952.
Bosch-Queralt, Mar; Fledrich, Robert & Stassart, Ruth M.
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Synaptic alterations in motor circuits relevant to the peripheral nerve disease Charcot-Marie-Tooth type 1A, talk at the Brain Dynamics Scientific Day, September 2023
Bosch-Queralt, M.
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The motor circuitry in CMT1A disease, talk at the PNS Meeting, Leipzig, April 2023
Bosch-Queralt, M.
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Alterations in Spinal Motor Circuits in CMT1A, Poster presentation and published abstract, Research Festival for Life Science, Leipzig, 2024
Kraft J., Schmidt J., Haidacher K., Rosenstiel L., Schwab M. H., Stassart R. M., Fledrich R. & Bosch-Queralt M.
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The role of Neuregulin-1 in the development of peripheral motor circuits, Poster presentation and published abstract, Research Festival for Life Science, Leipzig, 2024
Kummer B., Schwab M. H., Fledrich R., Stassart R. M. & Bosch-Queralt M.
