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1.
Brain Pathol ; 33(6): e13192, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37552802

RESUMEN

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model.


Asunto(s)
Enfermedad de Leigh , Enfermedades Mitocondriales , Humanos , Ratones , Animales , Niño , Enfermedad de Leigh/genética , Enfermedad de Leigh/patología , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , Macrófagos/patología , Tronco Encefálico/patología , Modelos Animales de Enfermedad
2.
Nat Commun ; 9(1): 843, 2018 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-29483589

RESUMEN

The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts. This refractory period limits the preBötC to very slow breathing frequencies. Inhibition integrated within the network is required to prevent overexcitation of preBötC neurons, thereby regulating the refractory period and allowing rapid breathing. In vivo, sensory feedback inhibition also regulates the refractory period, and in slowly breathing mice with sensory feedback removed, activity of inhibitory, but not excitatory, neurons restores breathing to physiological frequencies. We conclude that excitation and inhibition are interdependent for the breathing rhythm, because inhibition permits physiological preBötC bursting by controlling refractory properties of excitatory neurons.


Asunto(s)
Interneuronas/fisiología , Bulbo Raquídeo/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Periodicidad , Respiración , Animales , Retroalimentación Fisiológica , Femenino , Interneuronas/citología , Interneuronas/efectos de los fármacos , Masculino , Bulbo Raquídeo/efectos de los fármacos , Ratones , Ratones Transgénicos , Inhibición Neural/efectos de los fármacos , Neuronas/citología , Neuronas/efectos de los fármacos , Optogenética , Piridazinas/farmacología , Estricnina/farmacología , Vagotomía
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