Arsenic downregulates gene expression at the postsynaptic density in mouse cerebellum, including genes responsible for long-term potentiation and depression.
Arsenic (As) is a neurotoxin induces dysfunction of learning and memory. Research has indicated that cerebellum may be involved in arsenic-induced impairment of learning and memory. However, the molecular mechanisms that underlie these effects remain unclear. This study screened for the differentially expressed genes related to the long-term potentiation and long-term depression (LTP and LTD) at the cerebellar postsynaptic density (PSD) of mice following exposure to arsenic, and we provide evidence of the mechanism by which arsenic adversely affects the functions of learning and memory. Here, SPF mice were exposed to 1ppm, 2ppm and 4ppm As2O3 for 60 days. The ultrastructure of the synapses in cerebella of these mice was observed via transmission electron microscopy. The cerebellum global gene expression of mice exposed to 4ppm As2O3 was determined through GeneChip analysis. We used the web tool DAVID to analyze the Gene Ontology (GO) and KEGG pathways that were signiﬁcantly enriched among the differentially expressed genes. Our observations of synaptic ultrastructure showed that the thickness of the cerebellar PSD was reduced in mice exposed to arsenic. Go analysis revealed the PSD as a significantly altered cellular component. KEGG pathway analysis showed that LTP and LTD were affected by arsenic with highest statistical significance, and 20 differentially expressed genes were associated with them. Among these differentially expressed genes, significant decreases in the mRNA expressions of CaMKII, Gria1, Gria2, Grin1, Itpr1, Grm1 and PLCβ4 related to the LTP and LTD were found at the PSD of mouse cerebellum exposed to arsenic. The downregulation of these genes was further confirmed via real-time reverse transcription PCR or Western blot at 1ppm, 2ppm and 4ppm As2O3. Our results indicate that the 7 genes with in cerebellar PSDs may be involved in arsenic-induced neurotoxicity, including impairment of learning and memory.
Department of Occupational and Environmental of Health, Dalian Medical University, No 9 Western Section of Lvshun South Road, Dalian, LiaoNing, 116044, PR China; Dalian Municipal Center for Disease Control and Prevention, Dalian 116011, Liaoning, People's Republic of China.
Cong
C
Zhang
Department of Biochemistry, Dalian Medical University, PR China.
Sheng
S
Li
Dalian Municipal Center for Disease Control and Prevention, Dalian 116011, Liaoning, People's Republic of China.
Yahui
Y
Sun
Department of Occupational and Environmental of Health, Dalian Medical University, No 9 Western Section of Lvshun South Road, Dalian, LiaoNing, 116044, PR China.
Wei
W
Dong
Department of Occupational and Environmental of Health, Dalian Medical University, No 9 Western Section of Lvshun South Road, Dalian, LiaoNing, 116044, PR China. Electronic address: piao_fy_dy@163.com.
Fengyuan
F
Piao
Department of Dermatology, First Affiliated Hospital of Dalian Medical University, Dalian, LiaoNing, 116044, PR China.
Yongjun
Y
Piao
Department of Occupational and Environmental of Health, Dalian Medical University, No 9 Western Section of Lvshun South Road, Dalian, LiaoNing, 116044, PR China.
Shuang
S
Liu
Department of Obstetrics and Gynecology, No. 210 Hospital of PLA, Dalian, Liaoning 116021, China.
Huai
H
Guan
Department of Obstetrics and Gynecology, No. 210 Hospital of PLA, Dalian, Liaoning 116021, China; Department of Anatomy, Dalian Medical University, PR China.
Shengbo
S
Yu
D000818:Animals; D020261:Arsenic Poisoning / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects; D007858:Learning / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008568:Memory / Q000187:drug effects; D051379:Mice; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D010087:Oxides / Q000633:toxicity*; D057907:Post-Synaptic Density / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors
D001152:Arsenicals; D010087:Oxides; D012333:RNA, Messenger; D000077237:Arsenic Trioxide
Arsenic; Gene expression; LTP and LTD; Learning and memory; Postsynaptic density