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.

Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice

“…Previous studies have explored the consequences of deleting PTEN using transgenic promoter-driven Cre expression in PTEN f/f mice, including Ca 2+ /calmodulin-dependent protein kinase II (CamKII), (Sperow et al, 2012), dopamine active transporter (DAT), (Diaz-Ruiz et al, 2009), glial fibrillary acid protein (GFAP), (Backman et al, 2001; Fraser et al, 2008; Fraser et al, 2004; Kwon et al, 2001; Wen et al, 2013; Yue et al, 2005), and neuron specific enolase (NSE), (Kwon et al, 2006; Takeuchi et al, 2013). The expression of each promoter (and therefore Cre recombinase) varies, with the earliest expression beginning at embryonic day 12.5 (E12.5) for NSE (Forss-Petter et al, 1990), E13.5 for GFAP (Brenner et al, 1994), E15 for DAT (Smits and Smidt, 2006), and postnatal day 4 for CamKII (Burgin et al, 1990).…”

PTEN: A molecular target for neurodegenerative disorders

“…To further explore the role of PTEN in PD, two groups generated transgenic mice with conditional deletion of PTEN in the dopaminergic system, and both models shared similar phenotypes [113]. In the first model, PTENloxP mice were mated with Slc6a3Cr transgenic mice carrying the cre -recombinase transgene, driven by the dopamine transporter (DAT) promoter for specific deletion in dopaminergic neurons by embryonic day 15 [113].…”

“…In the first model, PTENloxP mice were mated with Slc6a3Cr transgenic mice carrying the cre -recombinase transgene, driven by the dopamine transporter (DAT) promoter for specific deletion in dopaminergic neurons by embryonic day 15 [113]. At this stage, the dopaminergic neurons have fully differentiated.…”

“…Moreover PTEN depletion was found to protect against 6-OHDA mediated dopaminergic neurotoxicity [113]. The second research group crossed PTENloxP mice with transgenic mice with tifla deletion, a crucial ribosomal RNA transcription factor, leading to suppression of mTOR and a phenotype which mimic PD.…”

The Effects of PTEN Deletion on Cell Size and Plasticity in the Hippocampus

“…Temporal examination of PTEN showed variation over the development of these neurons, with the highest variability in the CA3 of the hippocampus and increased labeling in dendritic shafts paralleling synaptic stabilization (Perandones et al, 2004). In dopaminergic neurons, deletion of PTEN caused increased neuronal soma size, increased cell proliferation, inhibited apoptosis and thickened axon and dendritic projections in the ventral tegmental area (VTA), and substrantia nigra pars compacta (Diaz-Ruiz et al, 2009). Since a hallmark of these neurons is pruning through developmental cell death, and PTEN ablation prevents the apoptotic pathway activated by Akt, this would account for increased density.…”