Disturbances in the secretion of neurotransmitters in IA-2/IA-2beta null mice: changes in behavior, learning and lifespan.
Islet-associated protein 2 (IA-2) and IA-2beta are major autoantigens in type 1 diabetes and transmembrane proteins in dense core secretory vesicles (DCV) of neuroendocrine cells. The deletion of these genes results in a decrease in insulin secretion. The present study was initiated to test the hypothesis that this deletion not only affects the secretion of insulin, but has a more global effect on neuroendocrine secretion that leads to disturbances in behavior and learning. Measurement of neurotransmitters showed that norepinephrine, dopamine and 5-HT were significantly decreased in the brain of double knockout (DKO) mice (P<0.05 to <0.001). In tests evaluating anxiety-like behavior and conditioned-learning, the DKO mice showed a highly significant increase in anxiety-like behavior (P<0.01 to <0.001) and impairment of conditioned learning (P<0.01) as compared to WT mice. The DKO mice also displayed an increase in spontaneous and induced seizures (P<0.01) and age-related death. Contrary to the generally held view that IA-2 and IA-2beta are expressed exclusively in DCV, subcellular fractionation studies revealed that IA-2beta, but not IA-2, co-purifies with fractions rich in synaptic vesicles (SV), and that the secretion of dopamine, GABA and glutamate from the synaptosomes of the DKO mice was significantly decreased as was the number of SV (P<0.01). Taken together, these findings show that IA-2beta is present in both DCV and SV, and that the deletion of IA-2/IA-2beta has a global effect on the secretion of neurotransmitters. The impairment of secretion leads to behavioral and learning disturbances, seizures and reduced lifespan.
Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4322, USA.
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Nishimura
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Kubosaki
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Ito
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Notkins
D000367:Age Factors; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology*; D019921:Biotinylation / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology*; D004326:Drinking / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D019417:Hindlimb Suspension / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010433:Pentylenetetrazole; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency*; D011930:Reaction Time / Q000235:genetics; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000172:deficiency*; D045442:Rotarod Performance Test / Q000379:methods; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics; D016704:Synapsins / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism
D018687:Antidepressive Agents, Second-Generation; D007328:Insulin; D018377:Neurotransmitter Agents; D016704:Synapsins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D010433:Pentylenetetrazole