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.
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.
|Nagre, Nagaraja N; Subbanna, Shivakumar; Shivakumar, Madhu et al. (2015) CB1-receptor knockout neonatal mice are protected against ethanol-induced impairments of DNMT1, DNMT3A, and DNA methylation. J Neurochem 132:429-42|
|Kumar, J R; Basavarajappa, Balapal S; Vishwanath, B S et al. (2015) Biochemical and pharmacological characterization of three toxic phospholipase A2s from Daboia russelii snake venom. Comp Biochem Physiol C Toxicol Pharmacol 168:28-38|
|Subbanna, Shivakumar; Basavarajappa, Balapal S (2014) Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice. Exp Neurol 261:34-43|
|Subbanna, S; Nagre, N N; Shivakumar, M et al. (2014) Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice. Neuroscience 258:422-32|
|Kaur, Gurjinder; Sharma, Ajay; Xu, Wenjin et al. (2014) Glutamatergic transmission aberration: a major cause of behavioral deficits in a murine model of Down's syndrome. J Neurosci 34:5099-106|
|Basavarajappa, Balapal S; Nagre, Nagaraja N; Xie, Shan et al. (2014) Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice. Hippocampus 24:808-18|
|Basavarajappa, Balapal S; Subbanna, Shivakumar (2014) CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations. Hippocampus 24:178-88|
|Subbanna, Shivakumar; Shivakumar, Madhu; Psychoyos, Delphine et al. (2013) Anandamide-CB1 receptor signaling contributes to postnatal ethanol-induced neonatal neurodegeneration, adult synaptic, and memory deficits. J Neurosci 33:6350-66|
|Subbanna, Shivakumar; Shivakumar, Madhu; Umapathy, Nagavedi S et al. (2013) G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. Neurobiol Dis 54:475-85|
|Sadrian, B; Subbanna, S; Wilson, D A et al. (2012) Lithium prevents long-term neural and behavioral pathology induced by early alcohol exposure. Neuroscience 206:122-35|