Regulation of Hippocampal Synapse Formation and Function by Astrocytic Ephrin-B1: From Early Postnatal Development to Adulthood
- Author(s): Nguyen, Amanda Quetran
- Advisor(s): Ethell, Iryna M
- et al.
Neurons communicate with each other through synaptic connections. During development, it is essential that synapses undergo structural and functional modification. Improper development of neural connections can lead to neurodevelopmental disorders such as autism and intellectual disabilities. The synapse development process is comprised of three major steps: synaptogenesis, synapse pruning, and synapse stabilization. This refined process involves several key players, including astrocytes that come into close association with synapses, forming a tripartite complex with the pre- and postsynaptic structures. This association allows astrocytes to monitor and alter synaptic functions. Astrocytes communicate with synapses through either secreted factors or contact-mediated interactions. Release of specific astrocyte-derived gliotransmitters can affect both the structure and function of neurons. Besides affecting synaptogenesis and function, astrocytes are also involved in pruning of unnecessary synapses through contact-mediated phagocytosis; however, the exact “eat me” signal is still not known. My research investigates the role of astrocytic ephrin-B1 regulation of hippocampal synapses during early postnatal development, adulthood, and learning and memory consolidation. Ephrin-B1 is a membrane bound protein that acts as a ligand for EphB receptors, allowing for bi-directional signaling through cell-cell interactions. Astrocyte-neuronal interactions may allow astrocytes expressing ephrin-B1 to find and engulf synapses that are marked for removal by targeting unoccupied EphB receptors. Therefore, hippocampal circuitry may be modulated through the Eph/ephrin interaction between neuron and astrocytes. My studies indicate that astrocytic ephrin-B1 is a negative regulator of synapse formation. During early postnatal development, astrocytic ephrin-B1 is essential for proper excitatory/inhibitory (E/I) circuit formation, as loss of astrocytic ephrin-B1 resulted in enhanced excitatory function of CA1 pyramidal cells and diminished inhibitory function. Dysregulation of E/I balance impaired sociability and increased repetitive behaviors. In contrast, in adulthood astrocytic ephrin-B1 maintains synapse numbers. Ablation of astrocytic ephrin-B1 in adulthood resulted in increased excitatory synaptogenesis, particularly of immature synapses. Overabundance of immature synapses reduced CA1 pyramidal cell excitatory function. Interestingly, astrocytic ephrin-B1 functions in an activity dependent manner, specifically modulating synapse formation on activated neurons during learning and memory consolidation and recall. Together, these results suggest that astrocytic ephrin-B1 influences hippocampal circuits by restricting synapse formation.