Generation and characterization of an astrocyte specific conditional Gdi1 knock out mouse modelD Adamo, Patrizia (Avtor) Vardjan, Nina (Mentor) Zorec, Robert (Komentor) intellectual disabilityGdi1 mousebrain glucose uptakecognitionRAB GDP dissociation inhibitor-1 gene (GDI1) encodes for αGDI, a protein controlling the cycling of small GTPases orchestrating intracellular vesicular trafficking. Mutations in human GDI1 are responsible for X-linked intellectual disability (XLID). Adult mice lacking Gdi1 gene (Gdi1 KO), a model of XLID, showed working and associative memory deficits. The cognitive phenotype was explained by a large decrease in the reserve pool of synaptic vesicles (SVs) at the hippocampal synapses, resulting in a slow SV recovery after SV depletion. Thus, cognitive deficits may reflect the temporary depletion of the immediately available SVs. Because Gdi1 is ubiquitously expressed in neurons and in astrocytes, GDI1 mutations could affect trafficking of both cell types impairing astrocyte-neuron cross talk, leading to cognitive defects. To dissect the role of αGDI in neurons and in astrocytes, two conditional models in which Gdi1 is deleted respectively in neurons (CamkII-Cre+-Gdi1flox/Y) or in astrocytes (Glast-CreERT2+-Gdi1flox/Y) were generated. The CamkII-Cre+-Gdi1flox/Y mice phenocopied the Gdi1 KO mouse; instead, Glast-CreERT2+-Gdi1flox/Y mice have a selective impairment in working memory which was rescued by inhibiting glycolysis by 2-deoxy-D-glucose administration. Proteomic analysis showed significant changes in astrocyte-resident glucose handling enzymes. Imaging with [18F]-fluoro-2-deoxy-D-glucose revealed an increased D-glucose uptake in Gdi1-null brain, consistent with the facilitated D-glucose utilisation. These results support a new astrocyte-based mechanism in XLID, opening a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.20232023-05-24 07:15:03Doktorsko delo/naloga146338VisID: 217734COBISS_ID: 153240067sl