Motor and memory deficits in nestin-Cre Psip1 KO mice

Lens epithelium-derived growth factor (LEDGF), encoded by the Psip1 gene, is present throughout the body in two splice variants, LEDGF/p75 and LEDGF/p52. Histological analysis of fetal and adult human brains suggests a role in neurogenesis and differentiation of neuroepithelial stem cells. Furthermore, binding partners of LEDGF/p75, e.g. MeCP2 and PogZ are implicated in neurological diseases. To study the role of LEDGF in the brain, we developed a conditional Psip1 knock-out (KO) mouse model by crossbreeding Psip1Fl/Fl (doi:10.1101/gad.1565107) mice with nestin-Cre transgenic mice, resulting in a KO of both isoforms in the central nervous system. Histology and western blot analysis confirmed KO of LEDGF in the hippocampus, cerebellum, and spinal cord. Interestingly, western blot analysis provided evidence for differential splicing in different brain regions. The cerebellum has 2-fold more LEDGF/p75 than LEDGF/p52 while e.g. hippocampus has 10-fold more LEDGF/p52 than LEDGF/p75. To further characterize the KO model, we performed behavioral phenotyping using a batch of tests at different ages. Starting from 8 weeks of age, lower distance travelled and higher time immobile was evidenced in the open-field. Similarly, a lower latency to fall was observed in the rotarod. In addition, a decline in short‑term memory emerged from 20 weeks in the Y-maze delayed. In conclusion, the behavioral deficits in the conditional Psip1 KO model support the importance of LEDGF in normal brain function. Further research is ongoing to unravel the role of both isoforms in different brain regions and to study the basis of the motor and memory deficits.