UC Riverside

Although once thought of as simply supportive cells of the brain, astrocytes are now understood to be active participants in maintaining neuronal homeostasis through their glial-neuronal and glial-glial interactions. Indeed, astrocytes are exquisitely equipped to sense and respond to their environment, allowing them to perform a diverse array of essential activities such as ion and neurotransmitter homeostasis, and regulation of synaptogenesis, synapse elimination, and synapse plasticity. Developing and maintaining the proper number of synapses as well as an appropriate balance of excitatory and inhibitory synapses is critical for proper brain function. Indeed, excitatory-inhibitory (E/I) imbalance and impaired inhibition are hypothesized to underlie the development of hyperactive neuronal networks, driving the pathological phenotypes and behavioral impairments observed in neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and epilepsy. Dysfunctions in parvalbumin (PV) expressing inhibitory interneurons including reduced numbers and hypofunction of PV interneurons have been observed in several NDDs, prompting investigation into the mechanisms involved in regulating the formation, maintenance, and function of PV connections with excitatory pyramidal cells (PCs). The work presented in this thesis investigates the role of astrocytic ephrin-B1 in glial-neuronal interactions, with a particular focus on the development of inhibitory PV->PC synapses and glial-glial interactions, investigating the role of astrocytic ephrin-B1 in astrocyte-oligodendrocyte communications. Ephrin-B/EphB trans-synaptic signaling at excitatory synapses is well studied and has been shown to be critical for regulating excitatory synapse development and maturation, however the role of ephrin-B/EphB signaling in inhibitory synapses is less clear. Astrocytic ephrin-B1 was previously demonstrated to negatively regulate excitatory synapse development and positively regulate inhibitory synapse development, however the mechanism behind this regulation was unclear. My studies delineate a mechanism in which astrocytic ephrin-B1 facilitates the development of PV->PC inhibitory synapses through regulating the expression of its EphB receptor in PV boutons. My work also identifies a previously undescribed negative regulatory role of trans-synaptic EphB2/ephrin-B signaling at PV->PC inhibitory synapses. My work demonstrates that EphB2 expression in PV interneurons disrupts PV->PC inhibitory synapse development and that astrocytic ephrin-B1 positively regulates PV->PC synapse formation by interfering with EphB receptor signaling in PV boutons. Disruption of this regulatory mechanism by removal of astrocytic ephrin-B1 during development led to impaired inhibition in vivo as evidenced by increased seizure susceptibility and repetitive behaviors. My work also investigated astrocyte-oligodendrocyte interactions during development and suggests that astrocytic ephrin-B/EphB receptor signaling positively regulates oligodendrocyte development and myelination. Loss of astrocytic ephrin-B1 during development impaired oligodendrocyte and myelin gene expression, leading to impaired myelination and reduced numbers of oligodendrocytes in the corpus callosum, as well as the presence of a clasping phenotype. Together, these studies implicate astrocytic ephrin-B1 as an important regulator of several neurodevelopmental processes, including inhibitory PV->PC synaptogenesis and oligodendrocyte development.