Ethanol exposure is known to have adverse effects on the developing fetus. Ethanol use during the synaptogenesis period, which occurs over the third trimester of pregnancy in humans (1-14 days after birth in rodents), triggers apoptotic cell death. The use of ethanol affects hippocampal functions impairing synaptic plasticity, learning and memory. Our work during the KO1 award period has led to the hypothesis that ethanol exerts its effects on synaptic plasticity via increased production of endogenous cannabinoids [ECs;anandamide (AEA) and 2-arachidonylglycerol (2-AG)] in hippocampal neurons. Cannabinoids (CB) themselves, like ethanol inhibit synaptic plasticity and markedly exacerbate the apoptotic effects of ethanol in the developing brain. The CB-mediated synaptic activity during early brain development seems to affect brain maturation pathways that influence cognitive deficits. However, the cellular mechanism(s) by which ethanol affects EC-coupled pathways remains largely unknown. Our preliminary data suggest that ethanol administration during the synaptogenic period activates the cannabinoid type 1 (CB1R) receptor inducing neurodegeneration. In addition, the enhanced CB1R activity causes deficits in pCREB levels and synaptic plasticity in adult animals. The CB1R blockade rescues neurodegeneration in neonatal mice. It also rescues the synaptic dysfunction observed in adult animals. Our promising preliminary data, implicating ECs and CB1R-mediated mechanisms, underscores the importance of this research direction. Our central hypothesis is that ethanol-mediated activation of hippocampal CB1R pathways during synaptogenesis results in long-lasting deficits in synaptic plasticity. We propose three Specific Aims to address this hypothesis. The approach combines the use of CB1R null mice and the established immunological, biochemical methods and electrophysiology techniques.
In Specific Aim 1, we will investigate the effects of postnatal ethanol administration during the synaptogenesis period on the metabolic fate of AEA and 2-AG, and CB1Rs expression and function.
In Specific Aim 2, we will investigate as to how postnatal ethanol effects are coupled to the CB1R-dependent signaling pathways.
In Specific Aim 3, we will test whether the early postnatal ethanol exposure causes long lasting depression of hippocampal synaptic plasticity in adult animals. Understanding the molecular underpinnings of the EC pathway (s) in the hippocampus will help to develop potential CB1R targeted strategies for treating hippocampal abnormalities and memory and learning deficits that often result from alcohol abuse during pregnancy.

Public Health Relevance

It is hoped that better understanding of how ethanol exposure during CNS development alters endocannabinoid pathways in the hippocampus will lead to more effective strategies for the treatment of hippocampal abnormalities and related memory and learning deficits in children due to alcohol abuse during pregnancy, representing the most common developmental disability in the Western world. Additionally, the results of the proposed studies may be used by health care professionals in counseling pregnant women on the potential effects of alcohol consumption.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Neurotoxicology and Alcohol Study Section (NAL)
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Liu, Qi-Ying
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Nathan Kline Institute for Psychiatric Research
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Yuan, Aidong; Veeranna; Sershen, Henry et al. (2018) Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors. Transl Psychiatry 8:167
Joshi, Vikram; Subbanna, Shivakumar; Shivakumar, Madhu et al. (2018) CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol. Neuropsychopharmacology :
Subbanna, Shivakumar; Joshi, Vikram; Basavarajappa, Balapal S (2018) Activity-dependent Signaling and Epigenetic Abnormalities in Mice Exposed to Postnatal Ethanol. Neuroscience 392:230-240
Subbanna, Shivakumar; Nagre, Nagaraja N; Shivakumar, Madhu et al. (2018) CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice. Front Mol Neurosci 11:45
Basavarajappa, Balapal S; Shivakumar, Madhu; Joshi, Vikram et al. (2017) Endocannabinoid system in neurodegenerative disorders. J Neurochem 142:624-648
Basavarajappa, Balapal S; Subbanna, Shivakumar (2016) Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits. Brain Sci 6:
Subbanna, Shivakumar; Nagre, Nagaraja N; Shivakumar, Madhu et al. (2016) A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice. Physiol Behav 167:16-27
Subbanna, Shivakumar; Psychoyos, Delphine; Xie, Shan et al. (2015) Postnatal ethanol exposure alters levels of 2-arachidonylglycerol-metabolizing enzymes and pharmacological inhibition of monoacylglycerol lipase does not cause neurodegeneration in neonatal mice. J Neurochem 134:276-87
Basavarajappa, Balapal S (2015) Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling. Brain Sci 5:456-93
Yuan, A; Sershen, H; Veeranna et al. (2015) Functions of neurofilaments in synapses. Mol Psychiatry 20:915

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