Microglia, the immune cells of the central nervous system (CNS), have recently taken center stage in research due to their role in CNS diseases. An abnormal immune response during critical windows of development and consequent abnormal production of neuro-inflammatory mediators has an impact on the function and structure of the brain and contributes to the pathogenesis of several neurodevelopmental disorders such as Autism Spectrum Disorders. CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disease caused by de novo mutations in the X-linked CDKL5 gene. The consequent misexpression of the CDKL5 protein in the nervous system leads to a severe phenotype characterized by intellectual disability, autistic features, motor impairment, visual deficits, and early-onset epilepsy. To date, little is known about the etiology of CDD and no therapies are available. Recently, a major cytokine dysregulation proportional to clinical severity, inflammatory status, and redox imbalance was evidenced in plasma from CDD patients, suggesting a subclinical chronic inflammatory status in children affected by this pathology. However, it is still unknown whether such an inflammatory state may even be mirrored at the cerebral level and whether it can contribute to the pathophysiology of CDD. Cdkl5 knockout (KO) mouse models, recently created to investigate the role of CDKL5 in the etiology of CDD, recapitulate various features of the disorder. Previous studies have shown impaired neuronal maturation and survival in the hippocampus of Cdkl5 KO mice, but the knowledge of the substrates underlying these alterations is still limited. Interestingly, we found increased microglial activation in the brain of a mouse model of CDD, the Cdkl5 KO mouse. We found alterations of microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and increased STAT3 signaling in the brain of Cdkl5 KO mice. Remarkably, treatment with Luteolin (a natural anti-inflammatory flavonoid) recovers microglia alterations as well as impaired neuronal survival and maturation in Cdkl5 KO mice, and prevents increased NMDA-induced cell death in the hippocampus. Our results suggest that neuro-inflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of Luteolin as a treatment option in CDD patients.

Inhibition of microglia over-activation restores neuronal survival and maturation in a mouse model of CDKL5 deficiency disorder

Nicola Mottolese;Giuseppe Galvani;Manuela Loi;Giorgio Medici;Marianna Tassinari;Stefania Trazzi;Elisabetta Ciani
2021

Abstract

Microglia, the immune cells of the central nervous system (CNS), have recently taken center stage in research due to their role in CNS diseases. An abnormal immune response during critical windows of development and consequent abnormal production of neuro-inflammatory mediators has an impact on the function and structure of the brain and contributes to the pathogenesis of several neurodevelopmental disorders such as Autism Spectrum Disorders. CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disease caused by de novo mutations in the X-linked CDKL5 gene. The consequent misexpression of the CDKL5 protein in the nervous system leads to a severe phenotype characterized by intellectual disability, autistic features, motor impairment, visual deficits, and early-onset epilepsy. To date, little is known about the etiology of CDD and no therapies are available. Recently, a major cytokine dysregulation proportional to clinical severity, inflammatory status, and redox imbalance was evidenced in plasma from CDD patients, suggesting a subclinical chronic inflammatory status in children affected by this pathology. However, it is still unknown whether such an inflammatory state may even be mirrored at the cerebral level and whether it can contribute to the pathophysiology of CDD. Cdkl5 knockout (KO) mouse models, recently created to investigate the role of CDKL5 in the etiology of CDD, recapitulate various features of the disorder. Previous studies have shown impaired neuronal maturation and survival in the hippocampus of Cdkl5 KO mice, but the knowledge of the substrates underlying these alterations is still limited. Interestingly, we found increased microglial activation in the brain of a mouse model of CDD, the Cdkl5 KO mouse. We found alterations of microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and increased STAT3 signaling in the brain of Cdkl5 KO mice. Remarkably, treatment with Luteolin (a natural anti-inflammatory flavonoid) recovers microglia alterations as well as impaired neuronal survival and maturation in Cdkl5 KO mice, and prevents increased NMDA-induced cell death in the hippocampus. Our results suggest that neuro-inflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of Luteolin as a treatment option in CDD patients.
Proceedings NWG 2021
Nicola Mottolese, Giuseppe Galvani, Laura Gennaccaro, Manuela Loi, Giorgio Medici, Marianna Tassinari, Stefania Trazzi, Elisabetta Ciani
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/835195
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