PMID- 24662847 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20211021 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 269 DP - 2014 Jun 6 TI - The dense core vesicle protein IA-2, but not IA-2beta, is required for active avoidance learning. PG - 35-42 LID - S0306-4522(14)00236-X [pii] LID - 10.1016/j.neuroscience.2014.03.023 [doi] AB - The islet-antigens IA-2 and IA-2beta are major autoantigens in type-1 diabetes and transmembrane proteins in dense core vesicles (DCV). Recently we showed that deletion of both IA-2 and IA-2beta alters the secretion of hormones and neurotransmitters and impairs behavior and learning. The present study was designed to evaluate the contribution to learning of each of these genes by using single knockout (SKO) and double knockout (DKO) mice in an active avoidance test. After 5 days of training, wild-type (WT) mice showed 60-70% active avoidance responses, whereas the DKO mice showed only 10-15% active avoidance responses. The degree of active avoidance responses in the IA-2 SKO mice was similar to that of the DKO mice, but in contrast, the IA-2beta SKO mice behaved like WT mice showing 60-70% active avoidance responses. Molecular studies revealed a marked decrease in the phosphorylation of the cAMP response element-binding protein (CREB) and Ca(2+)/calmodulin-dependent protein kinase II (CAMKII) in the striatum and hippocampus of the IA-2 SKO and DKO mice, but not in the IA-2beta SKO mice. To evaluate the role of CREB and CAMKII in the SKO and DKO mice, GBR-12909, which selectively blocks the dopamine uptake transporter and increases CREB and CAMKII phosphorylation, was administered. GBR-12909 restored the phosphorylation of CREB and CAMKII and increased active avoidance learning in the DKO and IA-2 SKO to near the normal levels found in the WT and IA-2beta SKO mice. We conclude that in the absence of the DCV protein IA-2, active avoidance learning is impaired. CI - Published by Elsevier Ltd. FAU - Carmona, G N AU - Carmona GN AD - Experimental Medicine Section, Laboratory of Sensory Biology Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. FAU - Nishimura, T AU - Nishimura T AD - Experimental Medicine Section, Laboratory of Sensory Biology Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. FAU - Schindler, C W AU - Schindler CW AD - Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. FAU - Panlilio, L V AU - Panlilio LV AD - Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. FAU - Notkins, A L AU - Notkins AL AD - Experimental Medicine Section, Laboratory of Sensory Biology Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. Electronic address: anotkins@mail.nih.gov. LA - eng GR - Z99 DE999999/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20140321 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Dopamine Uptake Inhibitors) RN - 0 (Piperazines) RN - 90X28IKH43 (vanoxerine) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - EC 3.1.3.48 (Ptprn protein, mouse) RN - EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 8) SB - IM MH - Animals MH - Avoidance Learning/drug effects/*physiology MH - Blotting, Western MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism MH - Corpus Striatum/drug effects/*physiology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Dopamine Uptake Inhibitors/pharmacology MH - Heterozygote MH - Hippocampus/drug effects/*physiology MH - Homozygote MH - Male MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - Mice, Knockout MH - Phosphorylation/drug effects/physiology MH - Piperazines/pharmacology MH - Receptor-Like Protein Tyrosine Phosphatases, Class 8/genetics/*metabolism MH - Species Specificity PMC - PMC4038122 MID - NIHMS585838 OTO - NOTNLM OT - CAMKII OT - CREB OT - autoantigens OT - dopamine OT - type-1 diabetes COIS- The authors declare no conflicts of interest. EDAT- 2014/03/26 06:00 MHDA- 2015/02/13 06:00 PMCR- 2015/06/06 CRDT- 2014/03/26 06:00 PHST- 2013/11/14 00:00 [received] PHST- 2014/03/12 00:00 [revised] PHST- 2014/03/13 00:00 [accepted] PHST- 2014/03/26 06:00 [entrez] PHST- 2014/03/26 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] PHST- 2015/06/06 00:00 [pmc-release] AID - S0306-4522(14)00236-X [pii] AID - 10.1016/j.neuroscience.2014.03.023 [doi] PST - ppublish SO - Neuroscience. 2014 Jun 6;269:35-42. doi: 10.1016/j.neuroscience.2014.03.023. Epub 2014 Mar 21.