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Neuroinflammation rapidly triggers long-term modulation of synaptic transmission

University of British Columbia

Cognitive dysfunction and abnormal synaptic transmission are main characteristics of various brain disorders, including stroke, trauma and various neurodegenerative diseases. Neuroinflammation, known to influence synaptic function, plays an important role in all these brain disorders. Hypoxia is usually concurrent with neuroinflammation in these brain disorders. In peripheral systems, inflammation and hypoxia are interdependent on each other by sharing pathways at the initiation of downstream pathways leading to inflammatory responses. However, the interaction of inflammation and hypoxia in the CNS, and more importantly, whether this interaction can affect synaptic function, is still largely unknown. In Chapter 3, I performed field recording, whole cell recording, 2 photon imaging and biochemical measurements in acute hippocampal slices and found that inflammatory stimuli, either LPS or Aβ, interact with hypoxia to trigger a fast-onset (within 15 min) LTD of synaptic transmission. This neuroinflammation+hypoxia LTD is unusual in that it is independent of NMDARs, mGluRs or patterned synaptic activity. Neuroinflammatory stimulus activates NADPH oxidase by triggering subunits assembly and translocation to the plasma membrane. Hypoxia increases the level of lactic acid via glycolysis, resulting in an increase of lactic acid/pyruvate ratio and a consequent increase of NADPH/NADP⁺ ratio, which in turn boosts production of superoxide by NADPH oxidase. Superoxide subsequently activates PP2A, and ultimately leads to GluR2-mediated AMPAR endocytosis, resulting in LTD of synaptic transmission. In Chapter 4, I performed field recording and biochemical measurements in acute hippocampal slices and showed that LPS can impair the induction of LTP in a relatively rapid way (1 h pre-incubation). This blockage of LTP is mediated by the activation of microglial TLR4 and its associated MyD88-dependent signaling pathway. IL-1β released from microglia is the major factor in LPS-induced impairment of LTP. Taken together, our study discovered that neuroinflammation can rapidly induce long-term modulation of synaptic transmission through two distinct pathways. These findings represent novel mechanisms in which environmental stressors modulate synaptic transmission. Furthermore, our study contributes to our understanding of synaptic and cognitive dysfunctions in various brain disorders and suggests new therapeutic targets to alleviate memory loss in these disorders.

Text

2012-09-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/43253

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/