Novel Roles of the GPI-Anchor Cleaving Enzyme, GDE2, in Hippocampal Synaptic Morphology and Function

Hippocampal synaptic activity is tightly regulated to ensure appropriate synaptic function and plasticity, which are important for critical cognitive processes such as learning and memory. Altered hippocampal synaptic function can lead to cognitive and behavioral deficits observed in neurodegenerative diseases such as Alzheimer's disease (AD), necessitating a deeper fundamental understanding of hippocampal synaptic control mechanisms. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a surface transmembrane enzyme that cleaves the glycosylphosphatidylinositol anchor that tethers some proteins to the membrane. Mice lacking GDE2 (Gde2KO) display behavioral deficits in learning and memory that are hippocampal-dependent. However, roles of GDE2 in mouse hippocampal function are not known. Here, we show that GDE2 is expressed in pre- and postsynaptic compartments along apical dendrites in hippocampal CA1 cells. Gde2KO CA1 cells showed increased dendritic length and complexity and increased numbers of mushroom spines localized to the stratum radiatum. Furthermore, adult Gde2KOs displayed an increased frequency of miniature excitatory postsynaptic currents, impaired paired-pulse facilitation, and disrupted N-methyl-d-aspartate receptor (NMDAR)-mediated long-term depression (LTD). The phosphatidylinositol 3-kinase-AKT-glycogen synthase kinase 3 (PI3K-AKT-GSK3) signaling pathway, implicated in the inhibition of NMDAR-mediated LTD, was abnormally activated in the Gde2KO hippocampus, and inhibition of PI3K restored Gde2KO NMDAR-mediated LTD to WT levels. These observations identify GDE2 as an essential physiological regulator of CA1 synaptic morphology and hippocampal pre- and postsynaptic function, including the modulation of NMDAR-mediated LTD via the PI3K-AKT-GSK3 signaling axis.