Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

Abstract

One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS), which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD). Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD.

Keywords: CB1 receptors; brain development; fetal alcohol; intellectual disability; learning and memory; synaptic plasticity.

Figure 1

The potential enzymes involved in anandamide (AEA) biosynthesis. Stimulation of G-protein coupled receptor (GPCR) mediated adenylate cyclase and cAMP-dependent protein kinase (protein kinase A, PKA) potentiate N-acyltransferase (Ca²⁺-dependent transacylase) (NAT). A fatty arachidonic acid chain is transferred by NAT from the sn-1 position of phospholipids (phosphoglycerides, PG) to the primary amine of phosphatidylethanolamine (PE) in a Ca²⁺-dependent manner, forming an N-arachidonyl phosphatidylethanolamine (N-ArPE). This N-ArPE intermediate is then hydrolyzed by a phospholipase D (PLD)-like enzyme to generate AEA. In addition, potential alternative pathways for AEA formation from N-ArPE through 2-lysoNArPE and pAEA catalysed by sPLA2, lyso-PLD, ABDH4, GDE1 or PTPN22 and SHIP2 are shown (see text for details). Once synthesized, AEA can be metabolized into ethanolamine (EA) and arachidonic acid (AA) or transported to the outside of the cell through a process that has not yet been well characterized. Fatty acid binding proteins (FABPs) serve as intracellular carrier of AEA and play an important role in the AEA degradation by FAAH. EMT, ECmembrane transporter.

Figure 2

A proposed model suggesting that AEA/CB1R/ERK1/2/pCREB/Arc signaling regulates ethanol-induced neurodegeneration, resulting in neurobehavioral deficits in adult mice. P7 ethanol-enhances AEA levels (postsynaptic neuron) through transcriptional activation of NAPE-PLD and GDE1 enzymes. AEA acting through CB1Rs (AEA tone) (presynaptic neuron) may result in decreased glutamate release, which causes N -Methyl-d-aspartate (NMDA) receptor hypofunction, ERK1/2 and cAMP response element-binding protein (CREB) hypophosphorylation deficits in Arc expression and leads to neonatal neurodegeneration (condensed chromatin balls, electron microscopic image). Previous studies have shown that CB1R activation inhibits NMDA receptor function in several experimental models [283,284] and ethanol was shown to inhibit glutamatergic neurotransmission via CB1 receptor activation [285]. These events during postnatal development may disrupt the refinement of neuronal circuits [112,123] and lead to long-lasting deficits in synaptic plasticity and memory in adult animals. The inhibition of CB1Rs (AEA tone) prevents pERK1/2, CREB hypophosphorylation, deficits in Arc expression and neonatal neurodegeneration (Tau and caspase-3 cleavage), which results in normal neurobehavioral function in adult mice. Genetic ablation of the CB1R does not affect NMDA receptor antagonist-induced apoptosis, but does provide protection against ethanol-induced neonatal neurodegeneration, synaptic and memory deficits in adult mice. Thus, the putative AEA/CB1R/pERK1/2/pCREB/Arc signaling mechanism may have a potential regulatory role in neuronal function in the developing brain and may be a valuable therapeutic target for FASD.

Figure 3

Molecular events leading to loss of learning and memory as found in FASD. Depending on the developmental stage, pattern, concentration and duration of prenatal ethanol exposure can lead to molecular alterations (for example, activity of growth factors, changes in the regulation of gene expression, changes in adhesion, changes in endocannabinoid system) and impaired in neuronal communication and circuit formation. These events may lead to several transient and permanent changes in the hippocampus, including molecular changes, modifications in synaptic plasticity, morphological changes and neuronal loss. These prenatal ethanol-associated changes in the brain can potentially induce deficits in learning-and-memory processes found in the adult animals of FASD.