Early postnatal nicotine exposure disrupts the α2* nicotinic acetylcholine receptor-mediated control of oriens-lacunosum moleculare cells during adolescence in rats

Abstract

Maternal cigarette smoking during pregnancy and maternal nicotine exposure in animal models are associated with cognitive impairments in offspring. However, the underlying mechanism remains unknown. Oriens-lacunosum moleculare (OLM) cells expressing α2* nicotinic acetylcholine receptors (nAChRs) are an important component of hippocampal circuitry, gating information flow and long-term potentiation (LTP) in the CA1 region. Here we investigated whether early postnatal nicotine exposure alters the normal role of α2*-nAChR-expressing OLM cells during adolescence in rats. We found that early postnatal nicotine exposure significantly decreased not only the number of α2-mRNA-expressing interneurons in the stratum oriens/alveus, but also α2*-nAChR-mediated responses in OLM cells. These effects of nicotine were prevented by co-administration with the nonselective nAChR antagonist mecamylamine, suggesting that nicotine-induced activation, but not desensitization, of nAChRs mediates the effects. α2*-nAChR-mediated depolarization of OLM cells normally triggers action potentials, causing an increase in spontaneous inhibitory postsynaptic currents in synaptically connected pyramidal cells. However, these α2*-nAChR-mediated effects were profoundly reduced after early postnatal nicotine exposure, suggesting altered control of CA1 circuits by α2*-nAChR-expressing OLM cells. Furthermore, these effects were associated with altered excitatory neural activity and LTP as well as the loss of normal α2*-nAChR-mediated control of excitatory neural activity and LTP. These findings suggest the altered function of α2*-nAChR-expressing OLM cells as an important target of further study for identifying the mechanisms underlying the cognitive impairment induced by maternal smoking during pregnancy.

Impaired function of α2-containing nicotinic acetylcholine receptors on oriens-lacunosum moleculare cells causes hippocampus-dependent memory impairments

“…This could represent a significant restructuring of neuronal networks, caused by the persistent presence of nicotine at a time when nicotinic receptors are important modulators of the strength of newly forming excitatory synapses (Maggi et al, 2003; Maggi et al, 2004). Our previous study also showed that early nicotine exposure resulted in facilitated LTP (Nakauchi et al, 2015; Chen et al, 2016). Because LTP is a leading candidate for many forms of memory, we had expected that we would see an association of memory impairments with impaired LTP.…”

“…Additionally, in our rodent models we observed several changes to the way in which nAChR activation modulated CA1 activity and LTP (Nakauchi et al, 2015; Chen et al, 2016). In particular, we found that early postnatal nicotine exposure resulted in the functional loss of α2-containing nAChRs (α2* nAChRs) in oriens-lacunosum moleculare (OLM) cells (Chen et al, 2016), which are located in the stratum oriens and have projections into the stratum lacunosum-moleculare (Freund and Buzsaki, 1996).…”

“…OLM cells are unique in the hippocampus in that they express the α2* nAChR, which appears to be continuously activated in the presence of nicotine (Jia et al, 2009). We have previously shown that early life nicotine exposure impairs dorsal CA1-dependent memory, leads to the functional loss of α2* nAChRs in OLM cells, and disrupts the normal role of OLM cells in hippocampal CA1 function and LTP (Nakauchi et al, 2015; Chen et al, 2016). …”

“…In particular, we found that early postnatal nicotine exposure resulted in the functional loss of α2-containing nAChRs (α2* nAChRs) in oriens-lacunosum moleculare (OLM) cells (Chen et al, 2016), which are located in the stratum oriens and have projections into the stratum lacunosum-moleculare (Freund and Buzsaki, 1996). These interneurons receive cholinergic inputs from the medial septum, and can facilitate LTP at SC-CA1 synapses and block LTP at temporoammonic (TA) pathway synapses (Nakauchi et al, 2007; Leao et al, 2012).…”

“…One of the significant changes that has been observed in rodent hippocampal function following early postnatal nicotine exposure is an increase in CA1 depolarization following SC stimulation (Damborsky et al, 2012; Damborsky et al, 2015; Nakauchi et al, 2015; Chen et al, 2016). This could represent a significant restructuring of neuronal networks, caused by the persistent presence of nicotine at a time when nicotinic receptors are important modulators of the strength of newly forming excitatory synapses (Maggi et al, 2003; Maggi et al, 2004).…”