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Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure

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Abstract

Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.

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Acknowledgments

This work was supported by the Defense Threat Reduction Agency-Joint Science and Technology Office, Medical S&T Division (Grant Nos. CBM.NEURO.01.10.US.012 and CBM.NEURO.01.10.US.019) to AMM.

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The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Molecular and Cellular Biology Graduate Student Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    Tetsade CB Piermartiri

  2. Department of Neurology and Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    Hongna Pan, Jun Chen & Ann M. Marini

  3. Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, MD, 21010, USA

    John McDonough

  4. Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA

    Neil Grunberg

  5. Neurotoxicology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, MD, 21010, USA

    James P. Apland

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  1. Tetsade CB Piermartiri
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Piermartiri, T.C., Pan, H., Chen, J. et al. Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure. Neuromol Med 17, 251–269 (2015). https://doi.org/10.1007/s12017-015-8353-y

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