Titel: Cellular substrate of network dysfunction in mouse models of neuropsychiatric disorders
Sprache: Englisch
Autor*in: Chini, Mattia
Schlagwörter: PFC; neurodevelopment; electrophysiology; time series; neuropsychiatric disorders
Erscheinungsdatum: 2021
Tag der mündlichen Prüfung: 2021-06-17
It has long been hypothesized that the pathophysiology of neurodevelopmental disorders begins long before the emergence of an appreciable symptomatology. In this regard, the prefrontal cortex is thought of being a major player, and disturbances to its development have been implicated in several of such disorders. However, evidence sustaining this proposition is still scarce, and there is a lack of mechanistic insights. A crucial repercussion of this shortcoming is the lack of progress in identifying early disease biomarkers and, consequently, in the development of early therapies that might help altering the course of these conditions. In this thesis, I addressed this knowledge gap by studying the physiological and pathological early development of the rodent prefrontal cortex, and the therefrom depending cognitive abilities.
While rodents clearly lack the finesse of human cognition, and the translation of rodent research on neurodevelopmental disorders to human patients is certainly not without perils, they also offer remarkable opportunities. Rodents are altricial species compared
to humans, and are thus already accessible to investigations at a developmental stage that roughly corresponds to mid human gestation, a period of high vulnerability for neuropsychiatric disorders. Moreover, recent advances in genome manipulation and viral vector targeting allow not only to causally and specifically investigate specific brain structures and networks, but also better modeling of the genetic landscape of these diseases.
Employing an array of different mouse models of mental disorders, we report that, as hypothesized, the prefrontal cortex exhibits functional disturbances already in the first days after birth, and that these deficits are predictive of impaired cognitive abilities. A reduced hippocampal drive to the prefrontal cortex is upstream of these manifestations. Particularly severely affected are layer II/III pyramidal neurons, that are characterized by a simplified dendritic arborization and reduced synaptic density. In turn, this results in impaired prefrontal network oscillations. By chronically optogenetic stimulation of this same neuronal population and of prefrontal oscillations, we show that prefrontal oscillations are homeostatically regulated, and that an overabundant level of activity is equally detrimental to the development of cognitive abilities. Taken together, this data supports the notion that early prefrontal oscillations might be an early biomarker tracking the pathophysiology of neurodevelopmental disorders. Conclusively, in a mouse model that is characterized by systemic inflammation during pregnancy, we show that microglia cells, the resident brain immune cells, are involved in the processes that ultimately result in cognitive deficits. They display an altered morphology and engulf an excessive amount of synaptic terminals. Inhibition of their inflammatory response fully rescues the deficits affecting prefrontal network oscillations and the cognitive symptomatology. While still preliminary, this body of work might help establishing new principles in the development of pharmaceutical tools that could alter the course of neurodevelopmental disorders.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/9150
URN: urn:nbn:de:gbv:18-ediss-94447
Dokumenttyp: Dissertation
Betreuer*in: Hanganu-Opatz, Ileana
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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