The goal of the proposed studies is to define the mechanisms underlying synapse development and remodeling by delineating a new role of ephrin-B1 signaling in astrocyte- mediated synapse pruning. While several astrocyte-secreted factors have been implicated in synaptogenesis, molecular signals that trigger astrocyte-mediated synapse pruning remain undefined. Astrocytes are implicated in synaptic pruning that is associated with the developmental refinements of neuronal circuits and astrocyte dysfunctions are linked to the synapse pathology associated with neurodevelopmental disorders. Astrocytes also play an important role in brain repair following traumatic brain injury (TBI) by protecting neurons from glutamate excitotoxicity and by regulating the blood-brain barrier. However, little is known about astrocyte-derived signals that contribute to injury-induced brain rewiring and the mechanisms underlying long-term neuropsychological changes and memory loss following TBI. This project will address the fundamental question of how astrocytes can regulate circuit remodeling through innovative experiments targeting ephrin-B signaling in astrocytes. We hypothesize that ephrin-B1/EphB signaling is involved in astrocyte-mediated synapse development and remodeling of excitatory synapses following injury. Our preliminary results support this hypothesis and show a transient up-regulation of ephrin-B1 in reactive astrocytes in the hippocampus following brain injury, which coincides with a significant reduction in synapse numbers. Further, targeted ablation of ephrin-B1 from adult astrocytes accelerated synapse recovery after injury. These studies support a role of astroglial ephrin-B1 in injury- induced synapse remodeling and suggest that astroglial ephrin-B1 may act as a negative regulator of synaptogenesis. Indeed, astrocyte-specific ablation of ephrin-B1 triggered an increase in the number of functional glutamatergic synapses in the adult hippocampus, suggesting that astrocytic ephrin-B1 may mediate pruning of existing synapses or inhibit new synapse formation through its interaction with neuronal EphB receptors. To test our hypothesis, we propose (1) to determine the mechanism of ephrinB1 signaling in astrocyte- mediated synapse formation and elimination; and (2) to establish the role of astrocytic ephrin- B1 in functional recovery after brain injury. The proposed research will advance our understanding of the fundamental mechanisms of astrocyte-mediated circuit remodeling by utilizing a broad range of innovative approaches. Since the disruption of neuronal circuits contribute to the pathophysiology of many neurologic diseases, the proposed work will inform future studies of the mechanisms underlying both neurodevelopmental disorders and neurodegenerative diseases.
The goals of our research are central to fully understanding how the synaptic remodeling of brain circuits work and to discovering new mechanisms that are essential for recovery after brain injury. In particular, we propose to study the mechanisms of contact-mediated astrocyte- neuron interactions that are important to our understanding of both circuit formation and remodeling, having implications for both neurodevelopmental disorders and neurodegenerative diseases. Our proposed research program will also benefit brain injury research by elucidating the long-term functional consequences of altered synaptic connectivity on brain function and neuropsychological changes, using clinically relevant behavioral and neuroimaging tests.
Showing the most recent 10 out of 20 publications
