PMID- 36746627 OWN - NLM STAT- MEDLINE DCOM- 20230310 LR - 20240503 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 43 IP - 10 DP - 2023 Mar 8 TI - Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease. PG - 1797-1813 LID - 10.1523/JNEUROSCI.1333-22.2023 [doi] AB - Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca(2+) dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca(2+) dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca(2+) transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca(2+) signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca(2+)/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca(2+) responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca(2+) responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca(2+)-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia. CI - Copyright (c) 2023 Sompol et al. FAU - Sompol, Pradoldej AU - Sompol P AD - Sanders-Brown Center on Aging. AD - Departments of Pharmacology and Nutritional Sciences. FAU - Gollihue, Jenna L AU - Gollihue JL AD - Sanders-Brown Center on Aging. FAU - Weiss, Blaine E AU - Weiss BE AD - Sanders-Brown Center on Aging. AD - Departments of Pharmacology and Nutritional Sciences. FAU - Lin, Ruei-Lung AU - Lin RL AD - Departments of Pharmacology and Nutritional Sciences. FAU - Case, Sami L AU - Case SL AUID- ORCID: 0000-0002-1004-7246 AD - Departments of Pharmacology and Nutritional Sciences. FAU - Kraner, Susan D AU - Kraner SD AUID- ORCID: 0000-0002-1062-4007 AD - Sanders-Brown Center on Aging. FAU - Weekman, Erica M AU - Weekman EM AD - Sanders-Brown Center on Aging. AD - Physiology. FAU - Gant, John C AU - Gant JC AD - Sanders-Brown Center on Aging. AD - Departments of Pharmacology and Nutritional Sciences. FAU - Rogers, Colin B AU - Rogers CB AD - Sanders-Brown Center on Aging. FAU - Niedowicz, Dana M AU - Niedowicz DM AD - Sanders-Brown Center on Aging. FAU - Sudduth, Tiffany L AU - Sudduth TL AD - Sanders-Brown Center on Aging. AD - Physiology. FAU - Powell, David K AU - Powell DK AD - Neuroscience. FAU - Lin, Ai-Ling AU - Lin AL AD - Sanders-Brown Center on Aging. AD - Departments of Pharmacology and Nutritional Sciences. FAU - Nelson, Peter T AU - Nelson PT AD - Sanders-Brown Center on Aging. AD - Pathology, University of Kentucky College of Medicine, Lexington, Kentucky 40536. FAU - Thibault, Olivier AU - Thibault O AD - Sanders-Brown Center on Aging. AD - Departments of Pharmacology and Nutritional Sciences. FAU - Wilcock, Donna M AU - Wilcock DM AD - Sanders-Brown Center on Aging. AD - Physiology. FAU - Norris, Christopher M AU - Norris CM AD - Sanders-Brown Center on Aging cnorr2@uky.edu. AD - Departments of Pharmacology and Nutritional Sciences. LA - eng GR - P01 AG078116/AG/NIA NIH HHS/United States GR - R21 AG074146/AG/NIA NIH HHS/United States GR - RF1 AG027297/AG/NIA NIH HHS/United States GR - R01 AG058171/AG/NIA NIH HHS/United States GR - R01 NS097722/NS/NINDS NIH HHS/United States GR - UL1 TR001998/TR/NCATS NIH HHS/United States GR - R01 AG027297/AG/NIA NIH HHS/United States GR - P30 AG072946/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230206 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Transcription Factors) SB - IM MH - Mice MH - Male MH - Female MH - Animals MH - *Alzheimer Disease/metabolism MH - Astrocytes/metabolism MH - *Hyperhomocysteinemia/metabolism/pathology MH - Diet MH - Transcription Factors/metabolism PMC - PMC10010459 OTO - NOTNLM OT - Alzheimer's disease OT - Ca2+ OT - neurovascular coupling OT - reactive astrocytes OT - synapses OT - vascular dementia EDAT- 2023/02/07 06:00 MHDA- 2023/03/11 06:00 PMCR- 2023/03/08 CRDT- 2023/02/06 21:22 PHST- 2022/07/07 00:00 [received] PHST- 2023/01/25 00:00 [revised] PHST- 2023/01/31 00:00 [accepted] PHST- 2023/02/07 06:00 [pubmed] PHST- 2023/03/11 06:00 [medline] PHST- 2023/02/06 21:22 [entrez] PHST- 2023/03/08 00:00 [pmc-release] AID - JNEUROSCI.1333-22.2023 [pii] AID - JN-RM-1333-22 [pii] AID - 10.1523/JNEUROSCI.1333-22.2023 [doi] PST - ppublish SO - J Neurosci. 2023 Mar 8;43(10):1797-1813. doi: 10.1523/JNEUROSCI.1333-22.2023. Epub 2023 Feb 6.