Calcineurin/NFAT Signaling in Activated Astrocytes Drives Network Hyperexcitability in Aβ-Bearing Mice

Abstract

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer's disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured in vivo with microelectrode arrays and ex vivo brain slices, using whole-cell voltage clamp. VIVIT treatment in 5xFAD mice led to increased expression of the astrocytic glutamate transporter GLT-1 and to attenuated changes in dendrite morphology, synaptic strength, and NMDAR-dependent responses. The results reveal astrocytic CN/NFAT4 as a key pathologic mechanism for driving glutamate dysregulation and neuronal hyperactivity during AD.

Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease

“…The lack of SOCS3 effects on amyloid deposition is in contrast with our previous study reporting significantly reduced number of MXO4 + amyloid plaques in APP/PS1dE9 mice with SOCS3 (Ceyzériat et al, 2018). This result is also in opposition with two studies reporting lower amyloid deposition after inhibition of reactive astrocytes through the calcineurin-NFAT pathway (Furman et al, 2012;Sompol et al, 2017) or after STAT3 conditional knockout in astrocytes of APP/PS1dE9 mice (Reichenbach et al, 2019). The fact that the same experimental manipulation of reactive astrocytes (through the JAK2-STAT3 pathway), in two AD mouse models, have different effects on the same disease outcome (amyloid plaques), assessed with the same method (MXO4) underlines that astrocyte reaction is more complex than expected.…”

Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain

“…We have interpreted these transcriptional changes as directly consequent to neuronal CN expression, but it is important to note that microglia and astrocytes monitor the status of nearby neurons (Nimmerjahn et al 2005;Dall erac et al 2013) and crosstalk between these cell types likely mediates some of the observed effects of CN expression. In accord with this caveat, it is clear that expression of CN in glia promotes numerous phenotypic changes that can impact neurons (Furman et al 2016;Sompol et al 2017) and the transcriptional response to CN in astrocytes includes upregulation of transcripts (Norris et al 2005) in opposition to the down-regulation observed here, indicating important celltype specific differences in the CN pathway. Moreover, we postulate that neuroinflammatory signals may play a major role in neuronal and glial CN activation, potentially linking neuroinflammation to a specific molecular mechanism that affects the neurodegenerative phenotype.…”

Region‐specific deletions of the glutamate transporter GLT1 differentially affect nerve injury‐induced neuropathic pain in mice

“…Several mechanisms were reported to be responsible for downregulating GLT1 expression (Gegelashvili & Bjerrum, ). For instance, activated astrocytes exhibit reduced GLT1 expression (Sompol et al, ). Alternatively, IL‐1β triggers GLT1 endocytosis by activating protein kinase C (Yan, Yadav, Gao, & Weng, ).…”