title: Blockade of Astrocytic Calcineurin/NFAT Signaling Helps to Normalize Hippocampal Synaptic Function and Plasticity in a Rat Model of Traumatic Brain Injury.
abstract: Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury. NFAT4, but not NFAT1, exhibited extensive labeling in astrocytes and was found throughout the axon/dendrite layers of CA1 and the dentate gyrus. Blockade of the astrocytic CN/NFAT pathway in rats using adeno-associated virus (AAV) vectors expressing the astrocyte-specific promoter Gfa2 and the NFAT-inhibitory peptide VIVIT prevented the injury-related loss of basal CA1 synaptic strength and key synaptic proteins and reduced the susceptibility to induction of long-term depression. In conjunction with these seemingly beneficial effects, VIVIT treatment elicited a marked increase in the expression of the prosynaptogenic factor SPARCL1 (hevin), especially in hippocampal tissue ipsilateral to the CCI injury. However, in contrast to previous work on Alzheimer's mouse models, AAV-Gfa2-VIVIT had no effects on the levels of GFAP and Iba1, suggesting that synaptic benefits of VIVIT were not attributable to a reduction in glial activation per se. Together, the results implicate the astrocytic CN/NFAT4 pathway as a key mechanism for disrupting synaptic remodeling and homeostasis in the hippocampus after acute injury.
  
  
  CONCLUSIONS
  Similar to microglia, astrocytes become strongly "activated" with neural damage and exhibit numerous morphologic/biochemical changes, including an increase in the expression/activity of the protein phosphatase calcineurin. Using adeno-associated virus (AAV) to inhibit the calcineurin-dependent activation of the transcription factor NFAT (Nuclear Factor of Activated T cells) selectively, we have shown that activated astrocytes contribute to neural dysfunction in animal models characterized by progressive/chronic neuropathology. Here, we show that the suppression of astrocytic calcineurin/NFATs helps to protect synaptic function and plasticity in an animal model in which pathology arises from a single traumatic brain injury. The findings suggest that at least some astrocyte functions impair recovery after trauma and may provide druggable targets for treating victims of acute nervous system injury.
authors: Department of Pharmacology and Nutritional Sciences.
authors: Jennifer L
authors: JL
authors: Furman
authors: Sanders-Brown Center on Aging, and.
authors: Pradoldej
authors: P
authors: Sompol
authors: Sanders-Brown Center on Aging, and.
authors: Susan D
authors: http://orcid.org/0000-0002-1062-4007
authors: SD
authors: Kraner
authors: Department of Pharmacology and Nutritional Sciences, Sanders-Brown Center on Aging, and.
authors: Melanie M
authors: MM
authors: Pleiss
authors: Sanders-Brown Center on Aging, and.
authors: Esther J
authors: EJ
authors: Putman
authors: Sanders-Brown Center on Aging, and.
authors: Jacob
authors: http://orcid.org/0000-0002-5708-4677
authors: J
authors: Dunkerson
authors: Sanders-Brown Center on Aging, and.
authors: Hafiz
authors: H
authors: Mohmmad Abdul
authors: Sanders-Brown Center on Aging, and.
authors: Kelly N
authors: KN
authors: Roberts
authors: Sanders-Brown Center on Aging, and Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
authors: Stephen W
authors: SW
authors: Scheff
authors: Department of Pharmacology and Nutritional Sciences, Sanders-Brown Center on Aging, and cnorr2@uky.edu.
authors: Christopher M
authors: CM
authors: Norris
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001930:Brain Injuries / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; D019703:Calcineurin
keywords: astrocytes; brain injury; calcineurin; calcium; glia; synapse