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Microglia trigger the structural plasticity of GABAergic neurons in the hippocampal CA1 region of a lipopolysaccharide-induced neuroinflammation model

It is well-established that microglia-mediated neuroinflammatory response involves numerous neuropsychiatric and neurodegenerative diseases. While the role of microglia in excitatory synaptic transmission has been widely investigated, the impact of innate immunity on the structural plasticity of GABAergic inhibitory synapses is not well understood. To investigate this, we established an inflammation model using lipopolysaccharide (LPS) and observed a prolonged microglial response in the hippocampal CA1 region of mice, which was associated with cognitive deficits in the open field test, Y-maze test, and novel object recognition test. Furthermore, we found an increased abundance of GABAergic interneurons and GABAergic synapse formation in the hippocampal CA1 region. The cognitive impairment caused by LPS injection could be reversed by blocking GABA receptor activity with (-)-Bicuculline methiodide. These findings suggest that the upregulation of GABAergic synapses induced by LPS-mediated microglial activation leads to cognitive dysfunction. Additionally, the depletion of microglia by PLX3397 resulted in a decrease in GABAergic interneurons and GABAergic inhibitory synapses, which blocked the cognitive decline induced by LPS. In conclusion, our findings indicate that excessive reinforcement of GABAergic inhibitory synapse formation via microglial activation contributes to LPS-induced cognitive impairment.

 

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Your summary outlines a research study that investigates the impact of microglia-mediated neuroinflammatory response on the structural plasticity of GABAergic inhibitory synapses in the hippocampal CA1 region of mice. Here's a breakdown of the key findings and conclusions from the study:

1. **Research Focus:** The study aimed to understand the influence of innate immunity, particularly microglia, on the structural plasticity of GABAergic inhibitory synapses in the context of neuroinflammatory response.

2. **Experimental Model:** The researchers used a lipopolysaccharide (LPS) inflammation model in mice, inducing prolonged microglial response in the hippocampal CA1 region.

3. **Cognitive Deficits:** The LPS-induced inflammation was associated with cognitive deficits, as observed in behavioral tests including the open field test, Y-maze test, and novel object recognition test.

4. **Increased GABAergic Synapses:** The study found an increased abundance of GABAergic interneurons and GABAergic synapse formation in the hippocampal CA1 region following LPS-induced microglial activation.

5. **Cognitive Impairment Mechanism:** The cognitive impairment resulting from LPS injection was attributed to the upregulation of GABAergic synapses. Blocking GABA receptor activity with (-)-Bicuculline methiodide reversed these cognitive deficits.

6. **Microglia Depletion:** Depleting microglia using PLX3397 led to a decrease in GABAergic interneurons and inhibitory synapses. This depletion prevented the cognitive decline induced by LPS, suggesting that microglia play a crucial role in this process.

7. **Conclusion:** Excessive reinforcement of GABAergic inhibitory synapse formation due to microglial activation contributes to LPS-induced cognitive impairment. This finding highlights the intricate relationship between neuroinflammation, GABAergic synapses, and cognitive function.

This research provides valuable insights into the mechanisms underlying cognitive impairment associated with neuroinflammatory responses, shedding light on potential therapeutic targets for neuropsychiatric and neurodegenerative diseases involving microglial activation and GABAergic synapses.

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S7071 (+)-Bicuculline (+)-Bicuculline (d-Bicuculline) is a competitive antagonist of GABAA receptors with IC50 of 2 μM, also blocks Ca(2+)-activated potassium channels.

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