Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes

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.

Nicotine on the developing brain

“…The hippocampus is not fully mature by adolescence and nicotine continues to produce unique, age-dependent effects. Whereas acute nicotine treatment promotes CA3–CA1 synaptic potentiation in adult mice, it does not in adolescents [ 159 ]. Acute nicotine is also less effective in adolescents than adults at enhancing context pre-exposure facilitation, a hippocampal-dependent cognitive task [ 160 ].…”

MicroRNA Regulation of the Environmental Impact on Adolescent Neurobehavioral Development: A Systematic Review

“…Despite this, we have identified eight papers quantifying miRNAs at different points of adolescence and/or adulthood in untreated control groups to perform comparisons with experimental treated groups. Thus, the quantifications reported are relative values that do not allow us to evaluate the course of miRNA expression profiles changes during adolescence in the absence of the treatment applied (Takebayashi et al, 2014;Li et al, 2016;Liu et al, 2016;Xu et al, 2017Xu et al, , 2019Cattaneo et al, 2020;Zaidan et al, 2021;Stojanovic et al, 2022).…”

“…Although all the studies administered the drug during adolescence, some of them used extreme ages, ranging from very early adolescence such as PND21-31 (Cuesta et al, 2018;Cattaneo et al, 2020) to late adolescence at PND-50-57 (Wang et al, 2014). The majority, however, used standard age criteria, and some of them included several ages for comparison (Takebayashi et al, 2014;Stojanovic et al, 2022).…”

“…The authors reported also similar effects induced by methamphetamine at PND-50. Furthermore, nicotine abolishes hippocampal LTP (long-term potentiation) in KO mice with the deletion of miR-132 and miR-212 (Stojanovic et al, 2022). Finally, other miRNAs associated with drug exposure during adolescence in rats are miR-214, which is downregulated in the hippocampus after adolescent ketamine injections that also induce learning and memory deficits (Wang et al, 2014), and miR-23a, which is upregulated in the entorhinal cortex by injections of the synthetic cannabinoid HU210 (Hollins et al, 2014).…”

MicroRNA-Mediated Silencing Pathways in the Nervous System and Neurological Diseases

“…From a future perspective might be interesting to explore the role of SERBP1/Ago2 complex and miR-92 on KCC2 regulation in Rett syndrome and other neurological disorders. In a study from Austria, Stojanovic et al combined biophysical and pharmacological approaches to evaluate the miRNA-132/212 gene-deletion and nicotine stimulation age-dependent effect on synaptic plasticity in the mice hippocampus [ 5 ]. In addition, they investigated the effects of miRNA-132/212 gene-deletion in an established electrophysiological model of ischemia, indicating the miRNAs and oxygen-glucose deprivation are connected [ 6 ].…”