Distribution of Alox15 in the Rat Brain and Its Role in Prefrontal Cortical Resolvin D1 Formation and Spatial Working Memory.
Docosahexaenoic acid (DHA) is enriched in membrane phospholipids of the central nervous system (CNS) and has a role in aging and neuropsychiatric disorders. DHA is metabolized by the enzyme Alox15 to 17S-hydroxy-DHA, which is then converted to 7S-hydroperoxy,17S-hydroxy-DHA by a 5-lipoxygenase, and thence via epoxy intermediates to the anti-inflammatory molecule, resolvin D1 (RvD1 or 7S,8R,17S-trihydroxy-docosa-Z,9E,11E,13Z,15E,19Z-hexaenoic acid). In this study, we investigated the distribution and function of Alox15 in the CNS. RT-PCR of the CNS showed that the prefrontal cortex exhibits the highest Alox15 mRNA expression level, followed by the parietal association cortex and secondary auditory cortex, olfactory bulb, motor and somatosensory cortices, and the hippocampus. Western blot analysis was consistent with RT-PCR data, in that the prefrontal cortex, cerebral cortex, hippocampus, and olfactory bulb had high Alox15 protein expression. Immunohistochemistry showed moderate staining in the olfactory bulb, cerebral cortex, septum, striatum, cerebellar cortex, cochlear nuclei, spinal trigeminal nucleus, and dorsal horn of the spinal cord. Immuno-electron microscopy showed localization of Alox15 in dendrites, in the prefrontal cortex. Liquid chromatography mass spectrometry analysis showed significant decrease in resolvin D1 levels in the prefrontal cortex after inhibition or antisense knockdown of Alox15. Alox15 inhibition or antisense knockdown in the prefrontal cortex also blocked long-term potentiation of the hippocampo-prefrontal cortex pathway and increased errors in alternation, in the T-maze test. They indicate that Alox15 processing of DHA contributes to production of resolvin D1 and LTP at hippocampo-prefrontal cortical synapses and associated spatial working memory performance. Together, results provide evidence for a key role of anti-inflammatory molecules generated by Alox15 and DHA, such as resolvin D1, in memory. They suggest that neuroinflammatory brain disorders and chronic neurodegeneration may 'drain' anti-inflammatory molecules that are necessary for normal neuronal signaling, and compromise cognition.
Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore.|Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 119260, Singapore.
Suku-Maran
SM
Shalini
Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore.|Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 119260, Singapore.
Christabel Fung-Yih
CF
Ho
Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore.
Yee-Kong
YK
Ng
Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore.
Jie-Xin
JX
Tong
Department of Science, Singapore University of Technology and Design, Singapore, 487372, Singapore.
Eng-Shi
ES
Ong
Department of Pharmacology, National University of Singapore, Singapore, 119260, Singapore.
Deron R
DR
Herr
Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 119260, Singapore.|Department of Pharmacology, National University of Singapore, Singapore, 119260, Singapore.
Gavin S
GS
Dawe
Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore. wei_yi_ong@nuhs.edu.sg.|Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 119260, Singapore. wei_yi_ong@nuhs.edu.sg.
Wei-Yi
WY
Ong
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D065852:Spatial Memory / Q000502:physiology*
C518399:resolvin D1; D004281:Docosahexaenoic Acids; D001093:Arachidonate 15-Lipoxygenase
15 Lipoxygenase 1; DHA; Learning and memory; Long-term potentiation; Resolvin D1; Spatial working memory; Synaptic plasticity