Objective To explore the role of calmodulin-dependent protein kinase Ⅱ (CaMK Ⅱ )and extracellular signal-regulated kinase ( ERK) in the pathogenesis of autism spectrum disorders. Methods Female Sprague-Dawley rats were given a single intraperitoneal injection of sodium valproate (VPA,600 mg/kg) on 12.5 d after pregnancy,and their offspring were as the model group; while the other pregnancy rats were given normal saline,and their offspring were as the control group.Both groups were observed with the HE staining,immunohistochemistry of CaMK Ⅱ and ERK and image analysis 1,7,14 d and 28 d after birth. Results Compared with the control group,HE staining showed the number of cortical neurons decreased on 1 d and 7 d after birth in the model group,rapidly increased on 14 d after birth,and maintained in high level on 28d after birth.For immunohistochemistry,the integrated optical density (IOD) of CaMKⅡ and ERK were increased in cortex on 1~14 d after birth (P<0.001) in both groups,and were stable 28 d after birth (P>0.05).Compared with the control group,the IOD of CaMK Ⅱ and ERK increased much more at every time point (P<0.001) in the model group.CaMK Ⅱ and ERK were increased on 1 d,7 d (P<0.001),significantly increased on 14 d (P<0.001),and tended to be stable on 28 d after birth (P>0.05). Conclusion The expression of CaMKⅡ and ERK of cerebral cortex neurons increases in the autism model rats,especially in the early time.
Key words
autistic spectrum disorders /
pathogenesis /
signal pathway /
calmodulin-dependent protein kinase Ⅱ /
extracellular signal-regulated kinase /
rat model
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References
[1] Lee PF,Thomas RE,Lee PA.Approach to autism spectrum disorder:Using the new DSM-V diagnostic criteria and the Can MEDS-FM framework[J].Can Fam Physician,2015,61(5):421-424.
[2] Walkup WG,Washburn L,Sweredoski MJ,et al.Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases[J].J Biol Chem,2015,290(8):4908-4927.
[3] Xing L,Larsen RS,Bjorklund GR,et al.Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex[J].Elife,2016,5(10):e11123.
[4] Subramanian M,Timmerman CK,Schwartz JL,et al.Characterizing autism spectrum disorders by key biochemical pathways[J].Front Neurosci,2015,24(9):313.
[5] Yufune S,Satoh Y,Takamatsu I,et al.Transient blockade of ERK phosphorylation in the critical period causes autistic phenotypes as an adult in mice[J].Sci Rep,2015,20(5):10252.
[6] Da Rosa MM,PingAn Y,Brambilla R,et al.Synaptic GluN2B/CaMKⅡ-α signaling induces synapto-nuclear transpor of ERK and jacob[J].Front Mol Neurosci,2016,9(10):66-79.
[7] Seese RR,Maske AR,Lynch G,et al.Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism[J].Neuropsychopharmacology,2014,39(7):1664-1673.
[8] Yin A,Qiu Y,Jia B,et al.The developmental pattern of the RAS/RAF/Erk1/2 pathway in the BTBR autism mouse model[J].Int J Dev Neurosci,2014,39(8):2-8.
[9] Gentile S.Drug treatment for mood disorders in pregnancy[J].Curr Opin Psychiatr,2011,24(1):34-40.
[10] Rasalam AD,Hailey H,Williams J,et al.Characteristics of fetal anticonvulsant syndrome associated autistic disorder[J].Dev Med Child Neurol,2005,47(8):551-555.
[11] Gentile S.Risks of neurobehavioral teratogenicity associated with prenatal exposure to valproate monotherapy:a systematic review with regulatory repercussions[J].CNS Spectr,2014,19(4):305-315.
[12] Rodier PM,Ingram JL,Tisdale B,et al.Linking etiologies in humans and animal models:studies of autism[J].Reprod Toxicol,1997,11(2):417-422.
[13] Guo W,Geolin L,Collins KA,et al.Elevated CaMKⅡα and hyperphosphorylation of Homer mediate circuit dysfunction in a Fragile X Syndrome mouse model[J].Cell Rep,2015,13(10):2297-2311.
[14] Kim KC,Kim P,Go HS,et al.Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder[J].J Neurochem,2013,124(6):832-843.
[15] Kalkman HO.Potential opposite roles of the extracellular signal-regulated kinase (ERK)Pathway in autism spectrum and bipolar disorders[J].Neuroscience and Biobehavioral Reviews,2012,7(8):2206-2213.
[16] Araki Y,Zeng M,Zhang M,et al.Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP[J].Neuron,2015,85(1):173-189.
[17] Alireza F,Dorothy JD,Eric R,et al.Mapk/Erk activation in an animal model of social deficits shows a possible link to autism[J].Molecular Autism,2014,57(5):1-12.
[18] Hans OK.Potential opposite roles of the extracellular signal-regulated kinase(ERK) pathway in autism spectrum and bipolar disorders[J].Neuroscience and Biobehavioral Reviews,2012,36(10):2206-2213.
[19] Faridar A,Jones-Davis D,Rider E,et al.Mapk/Erk activation in an animal model of social deficits shows a possible link to autism[J].Molecular Autism,2014,5(1):57-69.
[20] Park SM,Littleton JT,Park HR,et al.Drosophila homolog of human KIF22 at the autism-linked 16p11.2 loci influences synaptic connectivity at larval neuromuscular junctions[J].Exp Neurobiol,2016,25(1):33-39.
[21] Pucilowska J,Vithayathil J,Tavares EJ,et al.The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway[J].J Neurosci,2015,35(7):3190-3200.
[22] Satoh Y,Endo S,Nakata T,et al.ERK2 contributes to the control of social behaviors in mice[J].Neurosci,2011,31(33):11953-11967.
Funding
佳木斯大学研究生科技创新项目(YZ2016_003); 佳木斯大学科技创新团队(Cxtd-2013-02)
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