Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex
Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very freque...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119301184 |
| _version_ | 1818728699031191552 |
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| author | Brittany Short Lindsay Kozek Hannah Harmsen Bo Zhang Michael Wong Kevin C. Ess Cary Fu Robert Naftel Matthew M. Pearson Robert P. Carson |
| author_facet | Brittany Short Lindsay Kozek Hannah Harmsen Bo Zhang Michael Wong Kevin C. Ess Cary Fu Robert Naftel Matthew M. Pearson Robert P. Carson |
| author_sort | Brittany Short |
| collection | DOAJ |
| description | Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC. |
| first_indexed | 2024-12-17T22:34:08Z |
| format | Article |
| id | doaj.art-9d0b2e9d9ff44c1cac82019b22f54095 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T22:34:08Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9d0b2e9d9ff44c1cac82019b22f540952022-12-21T21:30:07ZengElsevierNeurobiology of Disease1095-953X2019-09-0112993101Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complexBrittany Short0Lindsay Kozek1Hannah Harmsen2Bo Zhang3Michael Wong4Kevin C. Ess5Cary Fu6Robert Naftel7Matthew M. Pearson8Robert P. Carson9Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, United StatesDepartment of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, United States; Vanderbilt Brain Institute, Vanderbilt University, United StatesDepartment of Pathology, Vanderbilt University Medical Center, United StatesDepartments of Neurology, Pediatrics, and Neuroscience, Washington University School of Medicine, United StatesDepartments of Neurology, Pediatrics, and Neuroscience, Washington University School of Medicine, United StatesDepartment of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, United States; Vanderbilt Brain Institute, Vanderbilt University, United StatesDepartment of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, United StatesDepartment of Neurosurgery, Vanderbilt University Medical Center, United StatesNeurosurgery, Sacred Heart Hospital, Pensacola, FL, United StatesDepartment of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, United States; Vanderbilt Brain Institute, Vanderbilt University, United States; Department of Pharmacology, Vanderbilt University Medical Center, United States; Corresponding author at: D-4105 MCN, 1161 21st Avenue South, Nashville, TN 37232-2594, United States.Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC.http://www.sciencedirect.com/science/article/pii/S0969996119301184Aquaporin-4EpilepsyTuberous sclerosis complexMouse |
| spellingShingle | Brittany Short Lindsay Kozek Hannah Harmsen Bo Zhang Michael Wong Kevin C. Ess Cary Fu Robert Naftel Matthew M. Pearson Robert P. Carson Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex Neurobiology of Disease Aquaporin-4 Epilepsy Tuberous sclerosis complex Mouse |
| title | Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex |
| title_full | Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex |
| title_fullStr | Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex |
| title_full_unstemmed | Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex |
| title_short | Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex |
| title_sort | cerebral aquaporin 4 expression is independent of seizures in tuberous sclerosis complex |
| topic | Aquaporin-4 Epilepsy Tuberous sclerosis complex Mouse |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119301184 |
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