Cognitive dysfunction induced by the deletion of NAA synthase Shati/Nat8l in mice

[Speaker] Kyosuke Uno:1
[Co-author] Kousuke Endo:1, Kazuyuki Sumi:1, Haddar Meriem:1, Yoshiaki Miyamoto:1, Shin-Ichi Muramatsu:2,3, Atsumi Nitta:1
1:Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan, 2:Division of Neurology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan, 3:Center for Gene & Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Background: Shati/Nat8l significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that the expression of Shati/Nat8l mRNA was increased following brain development in mice, while there was a reduction in the myelin basic protein (MBP) level in the prefrontal cortex of juvenile, but not adult, Shat/Nat8l knockout (Shati KO) mice. We found Shati KO mice demonstrates induces several behavioral deficits. Furthermore we also reported Shati/Nat8l affects neuronal axon outgrowth in the primary mice cultured neurons. Previous findings have suggested that Shati/Nat8l has essential roles in neuronal function. In this study, we carried out various behavioral and electrophysiological study using Shati KO mice to clarify the contribution of Shati/Nat8l on the cognitive function in mice.
Methods: We assessed the validity of behavioral test using Shati KO mice and wild type (WT) mice such as open field test, social interaction test, elevated plus maze test, Y-maze test and novel object recognition test. Next, hippocampal slices were prepared from Shati KO and WT mice, and recorded the evoked field excitatory postsynaptic potentials and long-term potentiation (LTP) using MED64 systems.
Results: In the open field test, Shati KO mice showed higher basal locomotor activity. Shati KO mice avoided social interaction with unfamiliar mice compared with WT mice. In the elevated plus maze test, Shati KO mice spent much longer time in open arms than WT mice. These behavioral changes were observed both male and female Shati KO mice. Interestingly, inpairment of cognitive dysfunction in the Y-maze and novel object recognition were observed only in Shati KO female mice. Furthermore, injection of adeno associated virus vector of Shati/Nat8l into hippocampal CA3 region of Shati KO ameliorated these cognitive dysfunctions in the female mice. Also in the electrophysiology test, the LTP of Shati KO mice were significantly decreased compared with wild type mice of both male and female mice.
Conclusions: These results suggest that Shati/Nat8L would be associated with cognitive function of mice and the impairment has some sexual differences.

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