title: The dense core vesicle protein IA-2, but not IA-2β, is required for active avoidance learning.
abstract: The islet-antigens IA-2 and IA-2β 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-2β 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-2β 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-2β 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-2β SKO mice. We conclude that in the absence of the DCV protein IA-2, active avoidance learning is impaired.
authors.affiliation: Experimental Medicine Section, Laboratory of Sensory Biology Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Carmona
authors.affiliation: Experimental Medicine Section, Laboratory of Sensory Biology Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Schindler
authors.affiliation: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Panlilio
authors.affiliation: 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.
authors.forename: A L
authors.initials: AL
authors.lastname: Notkins
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D006720:Homozygote; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
keywords: CAMKII; CREB; autoantigens; dopamine; type-1 diabetes