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 Ca2+ 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 Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/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.
|Number of pages||17|
|Journal||Journal of Neuroscience|
|State||Published - Mar 8 2023|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health (NIH)–National Institute on Aging Grants AG027297 and AG078116 to C.M.N., AG074146 to P.S, and AG058171 to O.T.; NIH Grant UL1TR001998 and University of Kentucky Neuroscience Research Priority Area to P.S.; NIH–National Institute of Neurological Disorders and Stroke Grant NS097722 to D.M.W.; the Hazel Embry Research Trust; and the Sylvia Mansbach Endowment for Alzheimer’s Disease Research. We thank Melanie Pleiss, who assisted with adeno-associated virus injections and MRI protocols.
Copyright © 2023 Sompol et al.
- Alzheimer’s disease
- neurovascular coupling
- reactive astrocytes
- vascular dementia
ASJC Scopus subject areas
- Neuroscience (all)