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

Abstract

Children of mothers who smoked during pregnancy are at significantly greater risk for cognitive impairments including memory deficits, but the mechanisms underlying this effect remain to be understood. In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired long-term hippocampus-dependent memory, functional loss of α2-containing nicotinic acetylcholine receptors (α2* nAChRs) in oriens-lacunosum moleculare (OLM) cells, increased CA1 network excitation, and unexpected facilitation of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Here we demonstrate that α2 knockout mice show the same pattern of memory impairment as previously observed in wild-type mice exposed to early postnatal nicotine. However, α2 knockout mice and α2 knockout mice exposed to early postnatal nicotine did not share all of the anomalies in hippocampal function observed in wild-type mice treated with nicotine during development. Unlike nicotine-treated wild-type mice, α2 knockout mice and nicotine-exposed α2 knockout mice did not demonstrate increased CA1 network excitation following Schaffer collateral stimulation and facilitated LTP, indicating that the effects are likely adaptive changes caused by activation of α2* nAChRs during nicotine exposure and are unlikely related to the associated memory impairment. Thus, the functional loss of α2* nAChRs in OLM cells likely plays a critical role in mediating this developmental-nicotine-induced hippocampal memory deficit.

α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice

“…Optogenetic studies using blue light activation of OLM a2 cells expressing channelrhodopsin in Chrna2-Cre mice, confirm that these GABAergic interneurons influence long-term potentiation within the CA1 hippocampus through GABAergic release (Leao et al 2012). Based on these findings, our current results provide additional evidence for the hypothesis that a2 nAChR subunit assemblies within the OLM a2 CA1 hippocampal brain region have functional consequences in synaptic plasticity, which may underlie hippocampus-dependent learning and memory in mice (Kleeman et al 2016).…”

“…The specific contributions of selective nAChR subunits influencing learning and memory, particularly during development, are poorly understood. Genetic deletion of a2 * nAChRs leads to subtle, yet discernible, potentiation of the first 2 d of nicotine self-administration, context specific withdrawal, emotional memory processing (Lotfipour et al 2013), and baseline deficits in hippocampusdependent memory (Kleeman et al 2016). Developmental dysregulation of neural circuits in the absence of a2 * nAChRs may be responsible for these modifications.…”

“…Within the dorsal through ventral CA1 of the hippocampus, a2 * nAChRs are located on oriens lacunosum moleculare (OLM) GABAergic interneurons (Sudweeks and Yakel 2000;Son and Winzer-Serhan 2006;Nakauchi et al 2007Nakauchi et al , 2015Leao et al 2012;Chen et al 2016;Kleeman et al 2016). Studies suggest that a2 * nAChRs play an important role in CA1 hippocampal OLM GABAergic interneurons (Ishii et al 2005;Nakauchi et al 2007Nakauchi et al , 2015Chen et al 2016;Kleeman et al 2016). Deletion of Chrna2 induces an absence of nicotine facilitation and suppression of hippocampal long-term potentiation (LTP) (Nakauchi et al 2007), likely via a dysregulation of OLM GABA neurotransmitter release (Leao et al 2012).…”

“…Deletion of Chrna2 induces an absence of nicotine facilitation and suppression of hippocampal long-term potentiation (LTP) (Nakauchi et al 2007), likely via a dysregulation of OLM GABA neurotransmitter release (Leao et al 2012). Furthermore, early developmental chronic nicotine exposure during peak mRNA expression periods of a2 * nAChRs (i.e., the first 2 wk of rodent life) is known to influence hippocampal synaptic plasticity and learning and memory during adolescence, likely via a2 * nAChRs (Nakauchi et al 2015;Chen et al 2016;Kleeman et al 2016). Our current study assessed whether deletion or functional enhancement of a2 * nAChRs are important for baseline and acute nicotine's effects on learning and memory processing.…”

Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex

“…Nicotine's depolarization of VIP cells was blocked by DHβE (0.5–1 μΜ; Figure b, paired t test: n = 10 cells, 4 mice, t (9) = 1.63, p = 0.14), but not by MLA (10 nM; Figure b; paired t test: n = 6 cells, 2 mice, t (5) = 7.75, p = 0.0006), demonstrating that nicotine's actions on VIP cells are mediated by β2‐containing nAChRs. The DHβE results indicate the likely involvement of α4β2 receptors due to their predominance in cortex, but do not preclude the involvement of relatively sparse α subunits, such as α2 or α5 (Kleeman et al, ; Koukouli et al, ). Overall, the results indicate that nicotine indirectly depolarizes Pyr cells and directly depolarizes VIP neurons via β2‐containing, but not α7, nAChRs.…”