UC Riverside

The hippocampus is a region of the brain required for associative memory formation, and hippocampal neurons retain a high level of synaptic plasticity in the adult that is thought to contribute to life-long learning in adults. Astrocytes play a critical role in synaptic plasticity and maintenance in the adult hippocampus and astrocyte dysfunctions are implicated in neurodevelopmental disorders associated with impaired learning and memory. In addition, many astrocyte-secreted factors are found to promote synaptogenesis and synaptic maturation, the close proximity of astrocytic processes to synapses suggests contact mediated factors contribute to synapse dynamics. This research investigates the role of astrocytic ephrin-B1 regulation in CA1 hippocampal synapses during memory formation. EphB receptors are expressed in both presynaptic CA1 and postsynaptic CA1 neurons, and trans-synaptic Eph/ephrin interactions have been shown to promote synaptic maturation by the clustering and recruitment of synaptic NMDA and AMPA receptors. These studies indicate that astrocytic ephrin-B1 mediates the elimination of immature hippocampal synapses possibly through competitive binding

with neuronal EphB receptors triggering the trans-phagocytosis of synapses inhibiting memory formation. Ablation of astrocytic ephrin-B1 increased the number of immature glutamatergic synapses in the SR of the CA1 hippocampus. In contrast, overexpression of ephrin-B1 decreased synapse number and remaining synapses were more mature than tdTomato expressing WT mice. Excess immature synapses in KO mice contributed to enhanced contextual recall by activity dependent maturation. KO mice had a significant increase in vGlut1/PSD95 co-localization after fear conditioning and deficits in synaptic AMPAR found in naïve mice were no longer seen after fear conditioning. In addition, OE mice had deficits in contextual recall. Diminished recall may be attributed to a reduction in synaptic connection after fear conditioning, as OE of astrocytic ephrin-B1 also inhibited activity dependent dendritic spine formation. Activity dependent AMPAR recruitment is also not observed in OE mice possibly due to a lack of immature synapses available for maturation prior to fear conditioning. In vitro studies suggest astrocytes eliminate synapses by trans-phagocytosis induced by neuronal EphB stimulated activation of ephrin-B1 reverse signaling.