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Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB<jats:sub>1<\/jats:sub>R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB<jats:sub>1<\/jats:sub>R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively. N-Arachidonoyl phosphatidylethanolamine\u2013phospholipase D (NAPE\u2013PLD), glycerophosphodiesterase (GDE1), and CB<jats:sub>1<\/jats:sub>R protein expression were enhanced by transcriptional activation of the genes encoding NAPE\u2013PLD, GDE1, and CB<jats:sub>1<\/jats:sub>R proteins, respectively. In addition, ethanol inhibited ERK1\/2 and AKT phosphorylation. The blockade of CB<jats:sub>1<\/jats:sub>Rs before ethanol treatment at P7 relieved ERK1\/2 but not AKT phosphorylation and prevented neurodegeneration. CB<jats:sub>1<\/jats:sub>R knock-out mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1\/2 phosphorylation. The protective effects of CB<jats:sub>1<\/jats:sub>R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA\/CB<jats:sub>1<\/jats:sub>R\/pERK1\/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.<\/jats:p>","DOI":"10.1523\/jneurosci.3786-12.2013","type":"journal-article","created":{"date-parts":[[2013,4,10]],"date-time":"2013-04-10T16:34:32Z","timestamp":1365611672000},"page":"6350-6366","source":"Crossref","is-referenced-by-count":94,"title":["Anandamide\u2013CB<sub>1<\/sub>Receptor Signaling Contributes to Postnatal Ethanol-Induced Neonatal Neurodegeneration, Adult Synaptic, and Memory 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