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Cassures double-brin de l'ADN des neurones : un rôle commun dans la physiopathologie de l'infection par le Bornavirus et l'inflammation chroniqu

Abstract : Viral infections and inflammation disrupt neuronal function, leading to behavioral and cognitive deficits. Although the underlying mechanisms remain to be fully uncovered, we already know that these pathological conditions impair neuronal epigenetics. Recently, DNA double-strand breaks (DSB) have been identified as un central regulator of neuronal epigenetic. In non-pathological conditions, neuronal activity induces the generation of DSB, which are quickly and efficiently repaired. The balance between DSB production and repair ensures a proper functioning of neurons. In this context, my Ph.D. project consisted in studying the impact of a viral infection or neuroinflammation on this balance and analyze their contribution of the latter on neuronal function or behavior. First, we studied the neuronal infection by the Borna disease virus (BoDV). This negative single stranded RNA neurotropic virus persists in the nervous system without inducing neuronal death. BoDV is singular as it replicates in the nucleus, in close interaction with cellular chromatin. We showed that BoDV infection increases DSB levels in primary cultures of rat neurons. We also discovered that DSB are used as platforms for the assembly of viral factories, thereby promoting viral replication. In addition, BoDV-infected neurons display reduced spontaneous electrical activity and impaired response to the stimulation of neurotransmission. At the molecular level, these alterations are linked to a loss of surface expression of the receptor to neurotransmitter glutamate, a receptor which is critically involved in neuronal plasticity and DSB production. Altogether, our results suggest the existence of a novel feedback loop mechanism to control viral replication, by inhibiting the induction of activity-dependent DSB to promote BoDV persistence. Independently of viral infections, neurological impairments are also observed in the course of chronic neuroinflammation. We asked whether the neurological symptoms that accompany chronic neuroinflammation may, in fact, result from alterations in DSB levels. In primary cultures of mouse neurons, we showed that interleukin-1ß (IL-1ß), one of the main proinflammatory cytokines in neuroinflammation, increase DSB levels in neurons. In order to study mouse behavior upon chronic treatment by IL-1ß, we have implemented an in-house behavioral core facility allowing for testing memory- and anxiety-related behaviors. We then carried out experiments of chronic exposure of mice to IL-1ß, using subcutaneously-implanted osmotic minipumps. We showed that IL-1ß treated-mice exhibit a lack of hippocampal dependent-spatial memory, accompanied by increased numbers of neurons with DSB in the hippocampus. Finally, thanks to conditional and inducible transgenic mouse models, we showed that knocking-out neuronal signaling pathways mediated by IL-1ß, or by DSB, prevent IL-1ß-dependent deleterious impact on memory. In conclusion, our work provides a better understanding of how, under pathological conditions, cognitive functions can be disrupted, and will allow ultimately, the identification of key factors of the regulatory processes of these mechanisms.
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Submitted on : Thursday, June 23, 2022 - 1:59:13 PM
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Florent Marty. Cassures double-brin de l'ADN des neurones : un rôle commun dans la physiopathologie de l'infection par le Bornavirus et l'inflammation chroniqu. Immunologie. Université Paul Sabatier - Toulouse III, 2021. Français. ⟨NNT : 2021TOU30275⟩. ⟨tel-03702850⟩

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