Abstract
Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212−/−) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3–CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212−/− mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3–CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212−/− mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212−/− mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.
Highlights
Nicotine addiction, as characterized by sustained and uncontrolled tobacco smoking, is behind millions of deaths worldwide and is causally related to conditions, such as coronary heart failure, atherosclerosis, brain stroke, and to malignancies [1–6]
Psychological interventions and pharmacotherapeutic attempts to handle nicotine addiction are poor in success, reflecting our scarcity of knowledge about the neurocognitive and molecular/functional effects of nicotine on the synaptic circuits underlying drug addiction
We examined the levels of expression of the proteins acetylcholinesterase (AChE), i.e., M1 muscarinic acetylcholine receptor (M1-mAChR), cAMP response element-binding protein (CREB), and phosphorylated CREB in the hippocampus of miRNA132/212−/− mice by conventional Western blot densitometric analyses, as previously described [30,42]
Summary
As characterized by sustained and uncontrolled tobacco smoking, is behind millions of deaths worldwide and is causally related to conditions, such as coronary heart failure, atherosclerosis, brain stroke, and to malignancies (such as oesophagus, lung, colon, and liver cancers) [1–6]. The involvement of the miRNA-132/212 cluster in synaptic transmission and plasticity has been previously associated to glutamatergic synaptic transmission in LTP experiments (see for example [44,46,57]); to learning and memory and BDNF, CREB, and MeCP2 signaling in vivo (see for example [36]); to altered levels of Abeta peptide, which is associated to Alzheimer’s disease [58]; and to other brain neuronal synaptic functions, as described by our group and our close collaborators [30,42,45]. Despite the fact that miRNAs and acethylcolinergic signaling regulate synaptic plasticity and mediate in the addictive response, the mechanisms by which addictive drugs influence the structural and functional remodeling of the hippocampal neuronal circuitry in an age-dependent manner remains poorly explored. We here provide experimental evidence proposing that miR-132/212 participate, in an age-dependent manner, in the regulation of the hippocampal responses to nicotine at selective neuronal circuits known to be relevant for both nicotine addiction and memory storage
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