Microinjection of Reelin into the medial prefrontal cortex improves MK801-induced memory impairment

[Speaker] Masahito Sawahata:1
[Co-author] Kanako Kitagawa:1, Yumi Tsuneura:1, Taku Nagai:1, Takao Kohno:2, Toshitaka Nabeshima:3,4, Mitsuharu Hattori:2, Kiyofumi Yamada:1
1:Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Japan, 2:Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan, 3:Advanced Diagnostic System Research Laboratory Fujita Health University, Graduate School of Health Sciences, Japan, 4:Aino University, Japan

[Background] Reelin is a huge secretory glycoprotein and plays an essential role in brain development. Recently, Reelin has attracted research attention in schizophrenia (SCZ). It has been reported that SCZ patients show reduced levels of reelin mRNA and protein in medial prefrontal cortex (mPFC) and other brain areas. Previously, our groups reported that intracerebroventriclular reelin has preventive effects on phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear how Reelin prevents cognitive dysfunction. In this study, we examine the effect of reelin in the mPFC on memory impairment induced by NMDA receptor antagonist MK801.
[Method] We used Expi293FTM expression system to prepare the recombinant Reelin. Expi293FTM cells were transfected with a full-length mouse WT Reelin or PDDK mutant which is degradation-resistant form of Reelin. For purified Reelin, cultured medium was incubated with anti-PA tag antibody coated-beads and concentrated by spin column. Recombinant Reelin was bilaterally injected into mPFC 5 days before the beginning of behavioral tests. As a SCZ model, we prepared MK801 (0.15 mg/kg)-injected mouse. MK801 was administered in a single intraperitoneal injection 30 min before behavioral test or training. To examine the effect of reelin on SCZ like behavior, we performed pre-pulse inhibition (PPI) test, novel object test (NORT) and Y-maze test.
[Results] To examine the role of reelin in mPFC, we injected recombinant Reelin into mPFC 5 days before the beginning of behavioral tests. Microinjection of Reelin into the mPFC had no effect on MK801-induced sensorimotor gating deficit in PPI test and impairment of short-term memory in Y-maze test. However, microinjection of Reelin into the mPFC significantly attenuated the long-term memory dysfunction in NORT. The ameliorating effect was also evident in PDDK mutant of Reelin.
[Conclusions] These results suggest that WT and PDDK Reelin prevent long-term memory impairment in the mPFC. On the other hand, microinjection of Reelin into the mPFC failed to sensorimotor gating and short-term memory dysfunction induced by MK801.

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