Effects of acute pro-inflammatory stimulation and 25-hydroxycholesterol on hippocampal plasticity & learning involve NLRP3 inflammasome and cellular stress responses

Neuroinflammation is an increasingly important target for therapeutics in neuropsychiatry and contributes to cognitive dysfunction, disability and death across a range of illnesses. We previously found that acute effects of pro-inflammatory stimulation with lipopolysaccharide (LPS) on hippocampal long-term potentiation (LTP), a form of synaptic plasticity involved in learning and memory, requires synthesis of the oxysterol, 25-hydroxycholesterol (25HC) and exogenous 25HC mimics effects of LPS. However, downstream mechanisms engaged by LPS and 25HC remain uncertain. Here we use rat hippocampal slices and in vivo behavioral studies to provide evidence that acute modulation of synaptic plasticity by both LPS and 25HC requires activation of the NLRP3 inflammasome, caspase-1 and interleukin-1 receptor. Furthermore, both LPS and 25HC engage cellular stress responses including synthesis of 5a-reduced neurosteroids and effects on plasticity are prevented by modulators of these responses. In studies of acute learning using a one-trial inhibitory avoidance task, inhibition of learning by LPS and 25HC are prevented by pre-treatment with an inhibitor of NLRP3. The present studies provide strong support for the role of 25HC as a mediator of pro-inflammatory stimulation on hippocampal synaptic plasticity and for the importance of NLRP3 inflammasome and caspase-1 activation in the deleterious effects of acute inflammation.