Impairment of hippocampal synaptic plasticity induced by pathological microglial activation

Abstract Background Neuroinflammation has demonstrated a key role in the pathogenesis of Alzheimer disease (AD). Among the innate immune cells, microglia are the primary players in neuroinflammation. When microglia is activated under pathological inflammatory conditions, it can lead to synaptic alterations thereby influencing the progression of AD. Among other mechanisms, an increased activation of microglial colony stimulating factor 1 receptor (CSF1R) can lead to pathological microglia activation in experimental models of AD (Olmos‐Alonso et al., 2016). In this work, using electrophysiological techniques, we investigated hippocampal synaptic transmission and plasticity in experimental models of neuroinflammation. We then tested whether the pharmacological manipulation of microglia activation was able to restore the neuroplasticity alterations associated with these models. Method The experiments were conducted using C57BL6/J mice of both sexes aged between 30‐ and 40‐days. Using electrophysiological approach ( field and whole cell patch clamp ), we performed recordings in area CA1 in response to stimulation of the Schaffer collaterals. We evaluated Long‐Term Potentiation (LTP) induced by theta‐burst stimulation. Responses were recorded for 1 hour after tetanization and measured as field Excitatory Post‐Synaptic Potential (fEPSP). Two in vitro inflammatory models were obtained applying Lipopolysaccharide (LPS) (10 μg/ml) or Aβ 1‐42 oligomers (200 nM). As a control, we tested the effect of Aβ 1‐42 with a scrambled sequence applied in the same condition of Aβ 1‐42. To inhibit the activation of microglia we used Pexidartinib (PLX‐3397) (10 μM), a specific inhibitor of activated microglia, and Minocycline (500 nM) a no‐specific blocker. Result Slices treated with Aβ 1‐42 and LPS showed impairment of LTP. Indeed, LTP was fully suppressed after exposition to oligomeric Aβ while no change of fEPSP was observed after incubation of slices with Aβ scrambled. Similarly, a selective inhibition of LTP was observed in the presence of LPS. Minocycline application reversed synaptic dysfunction in slices treated with Aβ 1‐42 and LPS. Preliminary data also indicate that PLX‐3397 rescues LTP impairment mediated by oligomeric Aβ. Conclusion Our data show a functional role of activated microglia in the synaptic plasticity alteration induced by neuroinflammation and suggest CSF1R as an emerging target in the treatment of AD.