title: Selective deletion of PTEN in dopamine neurons leads to trophic effects and adaptation of striatal medium spiny projecting neurons.
abstract: The widespread distribution of the tumor suppressor PTEN in the nervous system suggests a role in a broad range of brain functions. PTEN negatively regulates the signaling pathways initiated by protein kinase B (Akt) thereby regulating signals for growth, proliferation and cell survival. Pten deletion in the mouse brain has revealed its role in controlling cell size and number. In this study, we used Cre-loxP technology to specifically inactivate Pten in dopamine (DA) neurons (Pten KO mice). The resulting mutant mice showed neuronal hypertrophy, and an increased number of dopaminergic neurons and fibers in the ventral mesencephalon. Interestingly, quantitative microdialysis studies in Pten KO mice revealed no alterations in basal DA extracellular levels or evoked DA release in the dorsal striatum, despite a significant increase in total DA tissue levels. Striatal dopamine receptor D1 (DRD1) and prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while dopamine receptor D2 (DRD2) and preproenkephalin (PPE) mRNA levels remained unchanged. In addition, PTEN inactivation protected DA neurons and significantly enhanced DA-dependent behavioral functions in KO mice after a progressive 6OHDA lesion. These results provide further evidence about the role of PTEN in the brain and suggest that manipulation of the PTEN/Akt signaling pathway during development may alter the basal state of dopaminergic neurotransmission and could provide a therapeutic strategy for the treatment of Parkinson's disease, and other neurodegenerative disorders.
authors.affiliation: Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Ruiz
authors.forename: Agustin
authors.initials: A
authors.lastname: Zapata
authors.forename: Lufei
authors.initials: L
authors.lastname: Shan
authors.forename: YaJun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Tomac
authors.forename: Nasir
authors.initials: N
authors.lastname: Malik
authors.forename: Fidel
authors.initials: F
authors.lastname: de la Cruz
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Bäckman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004745:Enkephalins / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; D017448:Receptors, Dopamine D2; C033660:preproenkephalin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D004298:Dopamine