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Nicotine-induced lasting changes in glutamatergic synapses and attention

Nicotine-induced lasting changes in glutamatergic synapses and attention - Remco Westerink;  co-authored by Milou Dingemans.

Researchers from the CNCR and VUmc at the Neuroscience Campus Amsterdam (NCA - The Netherlands) described a mechanism involved in the long-lasting disturbances in attention following adolescent nicotine exposure this week in Nature Neuroscience.

Behavioural disturbances in adults are known to strongly correlate with adolescent nicotine use and most smokers start their habit during adolescence. Besides other obvious adverse health effects, cigarette smoking reduces working-memory and attention in adolescent smokers. Unfortunately, the adolescent brain may be particularly vulnerable for nicotine-induced changes.

Adolescent nicotine exposure was previously reported to affect cognitive performance and development of the brain, e.g., the development of the prefrontal cortex, the anterior part of the frontal lobes of the brain that is implicated in e.g., planning complex cognitive behaviours, decision making and attention.

The NCA study now reveals for the first time that in rats nicotine exposure during adolescence induced a long-lasting reduction in expression of a particular glutamate receptor, the mGluR2. Moreover, nicotine exposure during adolescence decreased the function of glutamate synapses in the prefrontal cortex. These changes parallel the observed impairment of attention induced by adolescent nicotine exposure.

Interestingly, this attention impairment in nicotine-exposed animals could be rescued by application of the glutamate receptor agonist LY379268, further illustrating the essential role of mGluR2 in the observed impairments. As none of these changes occurred when rats were exposed to nicotine only during adulthood, this study indicates that especially the adolescent brain is vulnerable for nicotine-induced changes lasting into adulthood.

Despite the importance of these NCA findings, which clearly demonstrate the involvement of mGluR2, this study gives rise to several important new questions. The lasting nicotine-induced reduction in mGluR2 level in synaptic terminals in the prefrontal cortex nicely parallels the changes in synaptic function as well as attentional behaviour, but what is the exact cause for the rather subtle but specific reduction in mGluR2 level?

Moreover, structural changes may also occur in other brain regions, as we have previously shown that the lasting behavioural effects induced by neonatal exposure to brominated diphenyl ethers are paralleled by a lasting reduction in hippocampal synaptic plasticity and a reduction in hippocampal glutamate receptors GluR1 and NR2B. Interestingly, the NCA nicotine study also showed a trend (p=0.051) towards downregulation of NR2B. These combined studies suggest that the expression of glutamate receptors is particularly sensitive to (behavioural) influences of neurotoxicants during distinct stages of brain development.

Equally important, is adolescence the only sensitive period for these nicotine-induced changes in attention and synaptic function? Studies from Eriksson’s lab previously showed that low dose neonatal nicotine exposure also induced lasting behavioural effects. Additional studies from Eriksson’s lab confirmed that the brain is particular vulnerable during early postnatal brain development.

It is thus likely that there are several distinct stages in life during which the brain is especially sensitive to disturbances, including chemical challenges. These stages apparently include the brain growth spurt and adolescence, but likely also in utero exposure. Identifying these different vulnerable stages will be of great importance for human risk assessment with respect to exposure to environmental pollutants and other neurotoxicants and the development of lasting behavioural effects, including attention deficits.