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STAT4 Play A Critical Role in Aging and High Fat Diet‐Associated Decline in Long‐Term, Activity‐Dependent Potentiation of Synaptic Transmission
Author(s) -
Stanton Patric K.,
Nadler Jerry L.,
Zhang Xiaolei,
Hollander Callie,
Ma Haoqin,
Yang Xinyuan,
D’silva Melinee,
Stahr Natalie,
Moriarty Alina,
Keeter Coles,
Galkina Elena V.
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r3145
Subject(s) - long term potentiation , schaffer collateral , biology , synapse , neuroscience , neurotransmission , synaptic plasticity , ltp induction , endocrinology , medicine , receptor
Aging and Alzheimer’s disease (AD) both exhibit declines in the magnitude of long‐term, activity‐dependent synaptic potentiation in humans and animals that correlate with declines in cognitive function and long‐term memory in a range of behavioral tasks. Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is essential for mediating T helper 1 cell differentiation and induction of inflammatory responses to IL‐12. STAT4 plays a vital role in signaling in a range of inflammatory diseases, including cardiovascular inflammation in diabetes, systemic lupus erythematosus and rheumatoid arthritis. It is, however, unknown what role STAT4 plays in central nervous system diseases such as AD, which also have significant inflammatory components to the progression of neurodegeneration. The present study examined the effects of elimination of STAT4 signaling in transgenic mice lacking myeloid cell‐specific STAT4 expression on the expression of long‐term potentiation (LTP) of synaptic transmission, and learning and memory, in mice fed normal versus high‐fat diets. Electrophysiological recordings from Schaffer collateral‐CA1 synapses in hippocampal slices from 3 or 24 week old LysM cre Stat4 fl/fl Ldlr ‐/‐ mice showed no differences in baseline synaptic transmission, paired‐pulse facilitation (PPF, a measure of presynaptic function), or LTP compared to age‐matched Stat4 fl/fl Ldlr ‐/‐ control littermates. Feeding mice a high cholesterol, high carbohydrate diet (DDC) diet from 8‐24 weeks of age resulted in marked, significant impairments in LTP compared to age‐matched mice fed a chow diet, without differences in basal transmission or PPF. In contrast to Stat4 fl/fl Ldlr ‐/‐ control mice, LysM cre Stat4 fl/fl Ldlr ‐/‐ mice receiving the same DDC diet were completely protected from DDC‐associated reductions in LTP. Our current behavioral data support the idea that DDC fed Ldlr ‐/‐ mice may experience cognitive and memory declines associated with early AD in comparison with LysM cre Stat4 fl/fl Ldlr ‐/‐ mice. Taken together, our data support an essential role for the transcription factor STAT4 in the sensitivity of the central nervous system to DDC ‐induced impairments in synaptic plasticity and potentially cognitive function, and suggest that STAT4 pathways are a promising new target for interventions to treat neurodegenerative diseases such as Alzheimer’s, where chronic neuroinflammation is a critical disease mediator.