Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory

PLOS ONE, Dec 2019

Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions.

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Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory

et al. (2012) Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory. PLoS ONE 7(11): e49998. doi:10.1371/journal.pone.0049998 Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory Mo nica Lo pez-Hidalgo 0 Karla Salgado-Puga 0 Reynaldo Alvarado-Martnez 0 Andrea Cristina Medina 0 Roberto A. Prado-Alcala 0 Jesu s Garca-Colunga 0 Jean-Pierre Mothet, CNRS - Universite Aix Marseille, France 0 1 Departamento de Neurobiolog a Celular y Molecular, Instituto de Neurobiolog a, Universidad Nacional Auto noma de Me xico, Campus Juriquilla, Quere taro, Me xico, 2 Departamento de Neurobiolog a Conductual y Cognitiva, Instituto de Neurobiolog a, Universidad Nacional Auto noma de Me xico , Campus Juriquilla, Quere taro, Me xico Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions. - Funding: This work was supported by Grants from Consejo Nacional de Ciencia y Tecnologa Mexico (81911 and 128259) and by a Grant from Direccio n General de Asuntos del Personal Academico, U.N.A.M. (IN204809). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The role of astrocytes in the central nervous system has been redefined, and they are now accepted as the third element in the synapses, alongside the pre- and postsynaptic neurons, astrocytes sense neuronal activity and respond with Ca2+ elevations which, in turn, can induce the release of gliotransmitters such as ATP, glutamate, and D-serine [1,2]. For instance, astrocytes surround a substantial portion of synapses which are largely glutamatergic [3]. In the hippocampus almost 60% of synapses have an apposed astrocytic process [4,5]. The release of the gliotransmitter Dserine, an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors [6,7], has been implicated in different types of activity-dependent synaptic plasticity including long-term potentiation and depression [8,9,10,11]. On the other hand, nicotine is considered to be the main addictive substance of tobacco, and it affects several brain functions due to its affinity for nicotinic acetylcholine receptors (nAChRs) [12]. Nicotine has effects on mnemonic functions; for example, nicotine improves long-term spatial memory, as measured in the Morris Water Maze [13,14] and procedural learning, evaluated in the one-trial step-through inhibitory-avoidance task [15,16]. Administration of nicotine also enhances cognitive functions in pathological conditions such as Alzheimers disease [13,17,18], and it reverses memory deficits caused by a lesion of the cholinergic system [19,20,21,22]. The effect of nicotine on hippocampal synaptic plasticity has been widely documented [20,22] and is known to involve the activation and desensitization of nAChRs present on interneurons and pyramidal neurons [23,24,25,26,27]. Furthermore, the fact that hippocampal astrocytes express nAChRs [28,29] and respond to nAChR agonists by increasing their intracellular Ca2+ concentration [30], raises the possibility that astrocytes could also be mediating nicotine effects in the hippocampus. Although there is no evidence of causality between long-term synaptic plasticity and memory, glial cells are critical for some types of memory [11,31,32]. Thus, glial cells could also mediate nicotine facilitation of long-term memory and the enhancement of synaptic transmission. In the present work, we show that glial cells, very likely through the release of D-serine, are essential for nicotine potentiation of synaptic transmission and nicotine facilitation of long-term memory. Materials and Methods Ethics Statement All procedures were carried out in strict accordance with the recommendations of the National Institutes of Health Guide for the Care and Use of Exper (...truncated)


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Mónica López-Hidalgo, Karla Salgado-Puga, Reynaldo Alvarado-Martínez, Andrea Cristina Medina, Roberto A. Prado-Alcalá, Jesús García-Colunga. Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory, PLOS ONE, 2012, Volume 7, Issue 11, DOI: 10.1371/journal.pone.0049998