title: Docosahexaenoic acid (DHA): a modulator of microglia activity and dendritic spine morphology.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department 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.
authors.forename: Philip K-Y
authors.initials: PK
authors.lastname: Chang
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, Room 1314, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. armen.khatchadourian@mail.mcgill.ca.
authors.forename: Armen
authors.initials: A
authors.lastname: Khatchadourian
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, Room 1314, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. anne.mckinney@mcgill.ca.|Department of Pharmacology & Therapeutics, Bellini Life Science Complex, McGill University, Room 167, 3649 Promenade Sir-William-Osler, Montreal, QC, H3G 0B1, Canada. anne.mckinney@mcgill.ca.
authors.forename: Rebecca Anne
authors.initials: RA
authors.lastname: McKinney
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building, Room 1314, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. dusica.maysinger@mcgill.ca.
authors.forename: Dusica
authors.initials: D
authors.lastname: Maysinger
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D066292:Lipid Droplets / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques; D000070780:Perilipin-2; D011134:Polysaccharides / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D002232:Carbocyanines; D008565:Membrane Proteins; D000070780:Perilipin-2; D011134:Polysaccharides; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D004281:Docosahexaenoic Acids; D009569:Nitric Oxide; D045304:Cytochromes c