Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months
Embryonic and early postnatal deletion of the gene phosphatase and tensin homolog (PTEN) results in neuronal hypertrophy, formation of aberrant neural networks and spontaneous seizures. Our previous studies document that deletion of PTEN in mature neurons also causes growth of cortical neuron cell b...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999612300205X |
| _version_ | 1797755782589054976 |
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| author | Jennifer M. Yonan Oswald Steward |
| author_facet | Jennifer M. Yonan Oswald Steward |
| author_sort | Jennifer M. Yonan |
| collection | DOAJ |
| description | Embryonic and early postnatal deletion of the gene phosphatase and tensin homolog (PTEN) results in neuronal hypertrophy, formation of aberrant neural networks and spontaneous seizures. Our previous studies document that deletion of PTEN in mature neurons also causes growth of cortical neuron cell bodies and dendrites, but it is unknown how this growth alters connectivity in mature circuits. Here, we explore consequences of deleting PTEN in a focal area of the dentate gyrus in adult male and female mice. PTEN deletion was accomplished by injecting AAV-Cre unilaterally into the dentate gyrus of double transgenic mice with lox-P sites flanking exon 5 of the PTEN gene and stop/flox tdTomato in the Rosa locus (PTENf/f/RosatdTomato). Focal deletion led to progressive increases in the size of the dentate gyrus at the injection site, enlargement of granule cell bodies, and increases in dendritic length and caliber. Quantitative analysis of dendrites by Golgi staining revealed dramatic increases in spine numbers throughout the proximo-distal extent of the dendritic tree, suggesting that dendritic growth is sufficient to induce new synapse formation by input neurons with intact PTEN expression. Tract tracing of input pathways to the dentate gyrus from the ipsilateral entorhinal cortex and commissural/associational system revealed that laminar specificity of termination of inputs is maintained. Mossy fiber axons from PTEN-deleted granule cells expanded their terminal field in CA3 where PTEN expression was intact and supra-granular mossy fibers developed in some mice. These findings document that persistent activation of mTOR via PTEN deletion in fully mature neurons re-initiates a state of robust cell-intrinsic growth, upending connectional homeostasis in fully mature hippocampal circuits. |
| first_indexed | 2024-03-12T17:51:08Z |
| format | Article |
| id | doaj.art-034015bd347e4a9d8e066c39971bfb3b |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-03-12T17:51:08Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-034015bd347e4a9d8e066c39971bfb3b2023-08-03T04:22:43ZengElsevierNeurobiology of Disease1095-953X2023-08-01184106190Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for monthsJennifer M. Yonan0Oswald Steward1Reeve-Irvine Research Center, University of California at Irvine, 837 Health Sciences Rd., Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California at Irvine, Irvine, CA 92697, USA; University of California at Irvine School of Medicine, Irvine, CA 92697, USAReeve-Irvine Research Center, University of California at Irvine, 837 Health Sciences Rd., Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California at Irvine, Irvine, CA 92697, USA; Department of Neurobiology & Behavior, University of California at Irvine, Irvine, CA 92697, USA; Department of Neurosurgery, University of California at Irvine, Irvine, CA 92697, USA; Center for the Neurobiology of Learning and Memory, University of California at Irvine, Irvine, CA 92697, USA; University of California at Irvine School of Medicine, Irvine, CA 92697, USA; Correspondence to: 1105 GNRF, University of California at Irvine, 837 Health Sciences Rd., Irvine, CA 92697, United States of America.Embryonic and early postnatal deletion of the gene phosphatase and tensin homolog (PTEN) results in neuronal hypertrophy, formation of aberrant neural networks and spontaneous seizures. Our previous studies document that deletion of PTEN in mature neurons also causes growth of cortical neuron cell bodies and dendrites, but it is unknown how this growth alters connectivity in mature circuits. Here, we explore consequences of deleting PTEN in a focal area of the dentate gyrus in adult male and female mice. PTEN deletion was accomplished by injecting AAV-Cre unilaterally into the dentate gyrus of double transgenic mice with lox-P sites flanking exon 5 of the PTEN gene and stop/flox tdTomato in the Rosa locus (PTENf/f/RosatdTomato). Focal deletion led to progressive increases in the size of the dentate gyrus at the injection site, enlargement of granule cell bodies, and increases in dendritic length and caliber. Quantitative analysis of dendrites by Golgi staining revealed dramatic increases in spine numbers throughout the proximo-distal extent of the dendritic tree, suggesting that dendritic growth is sufficient to induce new synapse formation by input neurons with intact PTEN expression. Tract tracing of input pathways to the dentate gyrus from the ipsilateral entorhinal cortex and commissural/associational system revealed that laminar specificity of termination of inputs is maintained. Mossy fiber axons from PTEN-deleted granule cells expanded their terminal field in CA3 where PTEN expression was intact and supra-granular mossy fibers developed in some mice. These findings document that persistent activation of mTOR via PTEN deletion in fully mature neurons re-initiates a state of robust cell-intrinsic growth, upending connectional homeostasis in fully mature hippocampal circuits.http://www.sciencedirect.com/science/article/pii/S096999612300205XPTENmTORDentate gyrusHippocampusGranule cellsEntorhinal cortex |
| spellingShingle | Jennifer M. Yonan Oswald Steward Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months Neurobiology of Disease PTEN mTOR Dentate gyrus Hippocampus Granule cells Entorhinal cortex |
| title | Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months |
| title_full | Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months |
| title_fullStr | Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months |
| title_full_unstemmed | Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months |
| title_short | Vector-mediated PTEN deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months |
| title_sort | vector mediated pten deletion in the adult dentate gyrus initiates new growth of granule cell bodies and dendrites and expansion of mossy fiber terminal fields that continues for months |
| topic | PTEN mTOR Dentate gyrus Hippocampus Granule cells Entorhinal cortex |
| url | http://www.sciencedirect.com/science/article/pii/S096999612300205X |
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