Review
A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development

https://doi.org/10.1016/j.prostaglandins.2011.07.002Get rights and content

Abstract

Docosahexaenoic acid (DHA), the n-3 essential fatty acid that is highly enriched in the brain, increases neurite growth and synaptogenesis in cultured mouse fetal hippocampal neurons. These cellular effects may underlie the DHA-induced enhancement of hippocampus-dependent learning and memory functions. We found that N-docsahexaenoylethanolamide (DEA), an ethanolamide derivative of DHA, is a potent mediator for these actions. This is supported by the observation that DHA is converted to DEA by fetal mouse hippocampal neuron cultures and a hippocampal homogenate, and DEA is present endogenously in the mouse hippocampus. Furthermore, DEA stimulates neurite growth and synaptogenesis at substantially lower concentrations than DHA, and it enhances glutamatergic synaptic activities with concomitant increases in synapsin and glutamate receptor subunit expression in the hippocampal neurons. These findings suggest that DEA, an ethanolamide derivative of DHA, is a synaptogenic factor, and therefore we suggest utilizing the term ‘synaptamide’. This brief review summarizes the neuronal production and actions of synaptamide and describes other N-docosahexaenoyl amides that are present in the brain.

Highlights

► N-docsahexanoylethanolamide (DEA) is a potent synaptogenic factor, and thus termed synapamide. ► Docosahexaenoic acid (DHA) is converted to DEA by fetal mouse hippocampal neurons. ► DEA is present in the mouse hippocampus. ► DEA stimulates neurite growth, synaptogenesis and glutamatergic synaptic activities. ► DEA increases synapsin and glutamate receptor subunit expression in the hippocampal neurons.

Introduction

Docosahexaenoic acid (DHA, 22:6n-3) is the n-3 polyunsaturated fatty acid that is highly enriched in the brain, including the hippocampus [1]. DHA accumulates in the brain during development, and this is associated with an increase in the hippocampus-related learning and memory functions [2]. Survival of the neurons, neurite development, synapse formation and glutamatergic synaptic activity are increased by DHA in embryonic hippocampal neuron cultures [3], suggesting that these cellular effects may underlie the DHA-induced enhancement in cognitive function. DHA also increases neurite growth in dorsal root ganglia neurons cultured from young and older rats [4], indicating that these actions of DHA are not limited to the hippocampus or the fetal period. It is important to determine the mechanism of these effects in order to gain further insight into the role of DHA in neurological development and function.

Most of the DHA in the tissues is esterified in phosphatidylserine (PS) and phosphatidylethanolamine (PE), phospholipids localized primarily in the inner leaflet of cell membranes. Some actions of DHA are due to effects on membrane lipid properties. These include effects of the DHA-enriched phospholipids on lipid domain structure [5], on proteins embedded in these membrane lipid domains [6], [7], or signaling pathways activated by interacting with these domains [8], [9], [10], [11]. Alternatively, DHA can be hydrolyzed from phospholipids by the Ca2+-independent phospholipase A2 (iPLA2) [12], and other functional effects are produced by metabolites synthesized from the released DHA. These include 10,17(S)-docosatriene that reduces neutrophil entry into inflammatory exudates [13], neuroprotectins that limit brain injury [14], [15] and cyclopentenone neuroprostanes that have anti-inflammatory effects [16].

N-docosahexaenoylethanolamide (DEA), another metabolite synthesized from DHA, is a member of the N-acylated amino acid or neurotransmitter class of lipid signaling molecules [17]. A number of these compounds have important bioactive properties in the brain; for example, the endocannabinoid N-arachidonoylethanolamide (AEA, anandamide) that modulates synaptic transmission and affects memory and behavior patterns [18], [19]. DEA is present in the brain, and the amount in mouse brain increases when the diet is supplemented with DHA [20], [21]. Our findings indicate that DEA is the mediator of the DHA-induced increase in neurite growth and synaptogenesis in hippocampal neurons, resulting in enhanced synaptic activity [22]. Therefore, we coin the term ‘synaptamide’ for DEA, a synaptogenic amide derivative of DHA. This brief review summarizes the formation and potent action of synaptamide in neurodevelopment and describes the currently available information about other N-docosahexaenoyl derivatives of amino acids and neurotransmitters that have been detected in the brain.

Section snippets

Neurite growth and synaptogenesis mediated by an amide form of DHA

DHA uniquely promotes neurite growth, synaptogenesis, synaptic protein expression and synaptic function in hippocampal neuron cultures obtained from day 18 (E-18) mouse fetuses [3]. The treatment of hippocampal neurons with DHA significantly increases the density of synapsin puncta (synapsins associated with synaptic vesicles) on neurites, suggesting improved synaptogenesis in developing neurons. Synapsins are a family of neuron-specific phosphoproteins associated with the membranes of synaptic

Biosynthesis of synaptamide in hippocampal neurons

The hippocampal neuron cultures were found to synthesize synaptamide from DHA [22], consistent with the inhibitor profile indicating that an amide metabolite of DHA mediates the DHA-induced effects on neurite growth and synaptogenesis. Fig. 2 contains mass spectrometry data showing that hippocampal cultures convert 13C22-DHA to a metabolite detected at m/z 394. The DEA standards, synthesized from DHA reacted with d4- or unlabeled ethanolamine, are detected at m/z 376 or m/z 372, respectively.

Synaptamide modulates neuritogenesis, synaptogenesis and synaptic function

Synaptamide is a potent mediator for the neuritogenic and synaptogenic effects of DHA. Fig. 3A shows the comparative effectiveness of synaptamide and DHA on neurite growth in 3 days-in vitro (DIV) cultures. Although a small increase in neurite growth relative to the control culture was noted with 0.5 μM DHA, a larger effect was produced by a 10-fold lower concentration of synaptamide. Fig. 3B shows the quantitative difference in neurite growth induced by synaptamide and DHA during 3 days in

Effects of dietary n-3 fatty acid deficiency on hippocampal N-acylethanolamides

Hippocampal neurite growth and synaptogenesis are impaired due to DHA depletion in offspring of female mice maintained on an n-3 fatty acid deficient diet [3], [44]. The deficient diet produced approximately 75% decrease in hippocampal DHA. This was accompanied by a 10-fold increase in the n-6 docosapentaenoic acid (DPAn-6). Accordingly, changes occurred in the levels of synaptamide and N-docosapentaenoyl ethanolamide (DPEA) in the hippocampi obtained from E-18 fetuses, as well as from

N-Docosahexaenoylamide derivatives

In addition to the N-acylethanolamides, more than 70 N-acylamide derivatives of amino acids and neurotransmitters have been detected in the brain [45], [46]. A number of these N-acylamides have bioactivity. For example, N-arachidonoylglycine inhibits pain [47], [48], is an insulin secretagogue [49], a ligand for the orphan receptors GPR18 and GPR92 [50], [51], and a reversible inhibitor of the glycine transporter GLYT2a [52]. N-palmitoylglycine increases Ca2+ influx in a dorsal root

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