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Docosahexaenoic acid (DHA): a modulator of microglia activity and dendritic spine morphology
Philip K-Y Chang1, Armen Khatchadourian2, Rebecca Anne McKinney3,4
1Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, Room 1314, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. philip.chang@mail.mcgill.ca.
Background:
Recent studies have revealed that excessive activation of microglia and inflammation-mediated neurotoxicity are implicated in the progression of several neurological disorders. In particular, chronic inflammation in vivo and exposure of cultured brain cells to lipopolysaccharide (LPS) in vitro can adversely change microglial morphology and function. This can have both direct and indirect effects on synaptic structures and functions. The integrity of dendritic spines, the postsynaptic component of excitatory synapses, dictates synaptic efficacy. Interestingly, dysgenesis of dendritic spines has been found in many neurological diseases associated with ω-3 polyunsaturated fatty acid (PUFA) deficiency and cognitive decline. In contrast, supplemented ω-3 PUFAs, such as docosahexaenoic acid (DHA), can partly correct spine defects. Hence, we hypothesize that DHA directly affects synaptic integrity and indirectly through neuron-glia interaction. Strong activation of microglia by LPS is accompanied by marked release of nitric oxide and formation of lipid bodies (LBs), both dynamic biomarkers of inflammation. Here we investigated direct effects of DHA on synaptic integrity and its indirect effects via microglia in the hippocampal CA1 region.
Methods:
Microglia (N9) and organotypic hippocampal slice cultures were exposed to the proinflammagen LPS (100 ng/ml) for 24 h. Biochemical and morphological markers of inflammation were investigated in microglia and CA1 regions of hippocampal slices. As biomarkers of hyperactive microglia, mitochondrial function, nitric oxide release and LBs (number, size, LB surface-associated proteins) were assessed. Changes in synaptic transmission of CA1 pyramidal cells were determined following LPS and DHA (25-50 μM) treatments by recording spontaneous AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs).
Results:
Microglia responded to LPS stimulation with a significant decrease of mitochondrial function, increased nitric oxide production and an increase in the formation of large LBs. LPS treatment led to a significant reduction of dendritic spine densities and an increase in the AMPA-mediated mEPSC inter-event interval (IEI). DHA normalized the LPS-induced abnormalities in both neurons and microglia, as revealed by the restoration of synaptic structures and functions in hippocampal CA1 pyramidal neurons.
Conclusion:
Our findings indicate that DHA can prevent LPS-induced abnormalities (neuroinflammation) by reducing inflammatory biomarkers, thereby normalizing microglia activity and their effect on synaptic function.
Insights
Docosahexaenoic acid (DHA) prevents lipopolysaccharide (LPS)-induced neuroinflammation by normalizing microglia activity and restoring synaptic function in the hippocampus. This omega-3 fatty acid protects against cognitive decline associated with neurological disorders.
Area of Science:
- Neuroscience
- Neuroinflammation
- Synaptic Plasticity
Background:
- Microglial activation and inflammation-mediated neurotoxicity contribute to neurological disorders.
- Dendritic spine dysgenesis is linked to cognitive decline and omega-3 polyunsaturated fatty acid (PUFA) deficiency.
- Docosahexaenoic acid (DHA) may counteract spine defects and influence neuron-glia interactions.
Purpose of the Study:
- To investigate the direct effects of DHA on synaptic integrity.
- To examine the indirect effects of DHA on synaptic integrity via microglia.
- To understand DHA's role in mitigating lipopolysaccharide (LPS)-induced neuroinflammation in the hippocampal CA1 region.
Main Methods:
- Organotypic hippocampal slice cultures and microglia (N9) were treated with LPS (100 ng/ml) for 24 hours.
- Biochemical and morphological markers of inflammation, including nitric oxide release and lipid bodies (LBs), were assessed.
- Synaptic transmission in CA1 pyramidal cells was measured via spontaneous AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs) following LPS and DHA (25-50 μM) treatments.
Main Results:
- LPS stimulation decreased microglial mitochondrial function and increased nitric oxide production and LB formation.
- LPS treatment reduced dendritic spine density and increased the mEPSC inter-event interval (IEI) in hippocampal CA1 neurons.
- DHA treatment normalized LPS-induced abnormalities in both microglia and neurons, restoring synaptic structures and function.
Conclusions:
- DHA prevents LPS-induced neuroinflammation by reducing inflammatory biomarkers.
- DHA normalizes microglial activity, mitigating their detrimental effects on synaptic function.
- DHA demonstrates potential therapeutic benefits for neurological conditions involving neuroinflammation and synaptic dysfunction.
