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Synaptic integration of transplanted fetal neurons into different neocortical environments
Synaptic integration of transplanted fetal neurons into different neocortical environments
Brain repair strategies are becoming more promising as the approach of neuron transplantation has been tested in clinical settings, e.g., as therapy for Parkinson disease (PD). One important feature that transplanted neurons need to fulfill is their precise synaptic integration into the existing host brain network to truly reconstruct neuronal circuits. Brain-wide connectivity as well as functionality of grafted neurons was shown to be highly adequate. Transplanted neurons were proven to become functional and integrate with high specificity into the host cortical circuitry in a condition of upper layer neuron ablation. However, there is still little knowledge about brain-wide input connectivity of grafted neurons particularly concerning conditions of severe brain injury that goes along with reactive gliosis (brain trauma) or neurodegenerative diseases and aging with slow progression of synapse loss. Therefore, in the course of this PhD project I examined host-graft connectivity using monosynaptic rabies virus (RABV) tracing in cortical stab wound (SW) injury, intact, and inflamed cortical conditions in adult mice to evaluate if and to which extent these conditions integrate transplanted fetal neurons. In addition, I investigated graft integration in brain environments of progressive amyloidosis going along with synapse loss as observed in Alzheimer’s disease (AD) and of healthy aging to explore any influence of the aging brain environment per se. Indeed, in all these different host environments the grafted fetal neurons survived, differentiated, and integrated by forming connections with the correct host input regions. Surprisingly, brain-wide connectivity analysis showed that the grafts received excessive inputs from local neurons in the SW-injured, amyloid-plaque loaded, and aged environment. On the other hand, there was quantitatively fewer neuron integration in intact young control brains and in brains exposed to Lipopolysaccharide (LPS) induced inflammation as opposed to the massive input connections observed in the other conditions. Thus, new neurons integrate independent of prior neuron loss or mild reactive gliosis as grafted cells formed connections even in conditions where neuron loss did not occur. State-of-the-art proteome analysis using mass spectrometry (MS) revealed the protein compositions of these host cortical environments promoting excessive synaptic integration. This data provides important and highly relevant insights for the design of cell-based therapies for brain trauma and neurodegenerative diseases that go along with synapse loss. Understanding the mechanism that promote synaptic integration will open new avenues to modulate certain parameters in order to achieve adequate functional repair of lost neurons and synaptic connections.
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Thomas, Judith
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Thomas, Judith (2021): Synaptic integration of transplanted fetal neurons into different neocortical environments. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)
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Abstract

Brain repair strategies are becoming more promising as the approach of neuron transplantation has been tested in clinical settings, e.g., as therapy for Parkinson disease (PD). One important feature that transplanted neurons need to fulfill is their precise synaptic integration into the existing host brain network to truly reconstruct neuronal circuits. Brain-wide connectivity as well as functionality of grafted neurons was shown to be highly adequate. Transplanted neurons were proven to become functional and integrate with high specificity into the host cortical circuitry in a condition of upper layer neuron ablation. However, there is still little knowledge about brain-wide input connectivity of grafted neurons particularly concerning conditions of severe brain injury that goes along with reactive gliosis (brain trauma) or neurodegenerative diseases and aging with slow progression of synapse loss. Therefore, in the course of this PhD project I examined host-graft connectivity using monosynaptic rabies virus (RABV) tracing in cortical stab wound (SW) injury, intact, and inflamed cortical conditions in adult mice to evaluate if and to which extent these conditions integrate transplanted fetal neurons. In addition, I investigated graft integration in brain environments of progressive amyloidosis going along with synapse loss as observed in Alzheimer’s disease (AD) and of healthy aging to explore any influence of the aging brain environment per se. Indeed, in all these different host environments the grafted fetal neurons survived, differentiated, and integrated by forming connections with the correct host input regions. Surprisingly, brain-wide connectivity analysis showed that the grafts received excessive inputs from local neurons in the SW-injured, amyloid-plaque loaded, and aged environment. On the other hand, there was quantitatively fewer neuron integration in intact young control brains and in brains exposed to Lipopolysaccharide (LPS) induced inflammation as opposed to the massive input connections observed in the other conditions. Thus, new neurons integrate independent of prior neuron loss or mild reactive gliosis as grafted cells formed connections even in conditions where neuron loss did not occur. State-of-the-art proteome analysis using mass spectrometry (MS) revealed the protein compositions of these host cortical environments promoting excessive synaptic integration. This data provides important and highly relevant insights for the design of cell-based therapies for brain trauma and neurodegenerative diseases that go along with synapse loss. Understanding the mechanism that promote synaptic integration will open new avenues to modulate certain parameters in order to achieve adequate functional repair of lost neurons and synaptic connections.