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Early postnatal nicotine exposure, a rodent model of smoking during pregnancy, affects hippocampal synaptic plasticity and memory. Here, we investigated the role of α2 nAChR-expressing OLM (α2-OLM) cells in LTP in unexposed and postnatal nicotine-exposed mice. We found that reduced α2 nAChR-dependent activation of OLM cells in α2 heterozygous knockout mice prevented LTP, whereas enhanced α2 nAChR-dependent activation of OLM cells in heterozygous knockin mice expressing hypersensitive α2 nAChRs facilitated LTP. Both optogenetic and chemogenetic activation of α2-OLM cells facilitated LTP as nicotine did. However, in postnatal nicotine-exposed mice, expressing chemogenetic hM3Dq receptors in α2-OLM cells, LTP was facilitated and both nicotinic and chemogenetic activation of α2-OLM cells prevented rather than facilitated LTP. These results demonstrate a critical role of α2-OLM cell activation in LTP as well as altered α2-OLM cell function in postnatal nicotine-exposed mice. To determine whether nicotine-mediated α2 nAChR activation in developing brains causes facilitated LTP and altered nicotinic modulation of LTP in adolescence, we used homozygous knockin mice expressing hypersensitive α2 nAChRs as a way to selectively activate α2-OLM cells. In the knockin mice, postnatal exposure to a low dose of nicotine, which had no effect on LTP in wild-type mice, is sufficient to cause facilitated LTP and altered nicotinic modulation of LTP as found in wild-type mice exposed to a higher dose of nicotine. Thus, the nicotine-mediated activation of α2 nAChRs on OLM cells in developing brains disrupts the α2-OLM cell-mediated control of LTP in adolescence that might be linked to impaired memory.

In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired hippocampus-dependent memory, but the underlying mechanism remains elusive. Given that hippocampal cholinergic systems modulate memory and rapid development of hippocampal cholinergic systems occurs during nicotine exposure, here we investigated its impacts on cholinergic function. Both nicotinic and muscarinic activation produce transient or long-lasting depression of excitatory synaptic transmission in the hippocampal CA1 region. We found that postnatal nicotine exposure impairs both the induction and nicotinic modulation of NMDAR-dependent long-term depression (LTD). Activation of muscarinic receptors decreases excitatory synaptic transmission and CA1 network activity in both wild-type and α2 knockout mice. These muscarinic effects are still observed in nicotine-exposed mice. M1 muscarinic receptor activity is required for mGluR-dependent LTD. Early postnatal nicotine exposure has no effect on mGluR-dependent LTD induction, suggesting that it has no effect on the function of m1 muscarinic receptors involved in this form of LTD. Our results demonstrate that early postnatal nicotine exposure has more pronounced effects on nicotinic function than muscarinic function in the hippocampal CA1 region. Thus, impaired hippocampus-dependent memory may arise from the developmental disruption of nicotinic cholinergic systems in the hippocampal CA1 region.

A high rate of heavy tobacco smoking among people with schizophrenia has been suggested to reflect self-medication and amelioration of cognitive dysfunction, a core feature of schizophrenia. NMDAR hypofunction is hypothesized to be a mechanism of cognitive dysfunction, and excessive schizophrenia-linked neuregulin 1 (NRG1) signaling through its receptor ErbB4 can suppress NMDAR function by preventing Src-mediated enhancement of NMDAR responses. Here we investigated whether chronic nicotine exposure in rats by subcutaneous injection of nicotine (0.5-1 mg/kg, twice daily for 10-15 days) counteracts the suppressive effect of NRG1β on NMDAR-mediated responses recorded from CA1 pyramidal cells in acute hippocampal slices. We found that NRG1β, which prevents the enhancement of NMDAR responses by the Src-family-kinase-activating peptide pYEEI in naive rats, failed to block the effect of pYEEI in nicotine-exposed rats. In naive rats, NRG1β acts only on GluN2B-NMDARs by blocking their Src-mediated upregulation. Chronic nicotine exposure causes enhanced GluN2B-NMDAR responses via Src upregulation and recruits Fyn for the enhancement of GluN2A-NMDAR responses. NRG1β has no effect on both enhanced basal GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses. Src-mediated enhancement of GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses initiate long-term potentiation (LTP) of AMPAR synaptic responses in naive and nicotine-exposed CA1 pyramidal cells, respectively. These results suggest that NRG1β suppresses LTP by blocking Src-mediated enhancement of GluN2B-NMDAR responses, but has no effect on LTP in nicotine-exposed rats. These effects of chronic nicotine exposure may counteract the negative effect of increased NRG1-ErbB4 signaling on the cellular mechanisms of learning and memory in individuals with schizophrenia, and therefore may motivate heavy smoking.

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.

Long-term potentiation (LTP) shows memory-like consolidation and thus becomes increasingly resistant to disruption by low-frequency stimulation (LFS). However, it is known that nicotine application during LFS uniquely depotentiates consolidated LTP. Here, we investigated how nicotine contributes to the disruption of stabilized LTP in the hippocampal CA1 region. We found that nicotine-induced depotentiation is not due to masking LTP by inducing long-term depression and requires the activation of GluN2A-containing NMDARs. We further examined whether nicotine-induced depotentiation involves the reversal of LTP mechanisms. LTP causes phosphorylation of Ser-831 on GluA1 subunits of AMPARs that increases the single-channel conductance of AMPARs. This phosphorylation remained unchanged after depotentiation. LTP involves the insertion of new AMPARs into the synapse and the internalization of AMPARs is associated with dephosphorylation of Ser-845 on GluA1 and caspase-3 activity. Nicotine-induced depotentiation occurred without dephosphorylation of the Ser-845 and in the presence of a caspase-3 inhibitor. LTP is also accompanied by increased filamentous actin (F-actin), which controls spine size. Nicotine-induced depotentiation was prevented by jasplakinolide, which stabilizes F-actin, suggesting that nicotine depotentiates consolidated LTP by destabilizing F-actin. α7 nicotinic acetylcholine receptor (nAChR) antagonists mimicked the effect of nicotine and selective removal of hippocampal cholinergic input caused depotentiation in the absence of nicotine, suggesting that nicotine depotentiates consolidated LTP by inducing α7 nAChR desensitization. Our results demonstrate a new role for nicotinic cholinergic systems in protecting potentiated synapses from depotentiation by preventing GluN2A-NMDAR-mediated signaling for actin destabilization.

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.

Fetal nicotine exposure from smoking during pregnancy causes long-lasting cognitive impairments in offspring, yet little is known about the mechanisms that underlie this effect. Here we demonstrate that early postnatal exposure of mouse pups to nicotine via maternal milk impairs long-term, but not short-term, hippocampus-dependent memory during adolescence. At the Schaffer collateral (SC) pathway, the most widely studied synapses for a cellular correlate of hippocampus-dependent memory, the induction of N-methyl-D-aspartate receptor-dependent transient long-term potentiation (LTP) and protein synthesis-dependent long-lasting LTP are not diminished by nicotine exposure, but rather unexpectedly the threshold for LTP induction becomes lower after nicotine treatment. Using voltage sensitive dye to visualize hippocampal activity, we found that early postnatal nicotine exposure also results in enhanced CA1 depolarization and hyperpolarization after SC stimulation. Furthermore, we show that postnatal nicotine exposure induces pervasive changes to the nicotinic modulation of CA1 activity: activation of nicotinic receptors no longer increases CA1 network depolarization, acute nicotine inhibits rather than facilitates the induction of LTP at the SC pathway by recruiting an additional nicotinic receptor subtype, and acute nicotine no longer blocks LTP induction at the temporoammonic pathway. These findings reflect the pervasive impact of nicotine exposure during hippocampal development, and demonstrate an association of hippocampal memory impairments with altered nicotinic cholinergic modulation of LTP, but not impaired LTP. The implication of our results is that nicotinic cholinergic-dependent plasticity is required for long-term memory formation and that postnatal nicotine exposure disrupts this form of plasticity.

Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory.

AimsStudying the normal role of nicotinic cholinergic systems in hippocampal synaptic plasticity is critical for understanding how cholinergic loss in Alzheimer's disease (AD) and tobacco use affect cognitive function. However, it is largely unknown how nicotinic cholinergic systems regulate the induction of long-term depression (LTD).Main methodsExtracellular field potential recordings were performed in hippocampal slices prepared from wild-type, α2, α7, and β2 knockout (KO) mice. Effects of nicotine and nicotinic antagonists on LTD induction in wild-type, α2, α7, and β2 KO mice were compared.Key findingsActivation of α7 nicotinic acetylcholine receptors (nAChRs) occurs during LTD-inducing stimulation to suppress LTD induction at CA3-CA1 synapses. Nicotine relieves this suppression, causing larger LTD. This nicotine effect was mediated by the activation of non-α7 nAChR subtypes, which were not activated by ACh released during LTD-inducing stimulation, and requires the presence of endogenous ACh-induced α7 nAChR activation. Furthermore, the effect of nicotine was prevented in the presence of mecamylamine, but not dihydro-β-erythroidine, and was still observed in both α2 KO and β2 KO mice.SignificanceThis is the first report to evaluate the involvement of different nAChR subtypes in LTD induction. Findings indicate the involvement of unique non-α7 nAChR subtypes, which have not been considered in the nicotinic modulation of hippocampal long-term potentiation, in the control of LTD induction. The implication of our results is that the loss of cholinergic projections to the hippocampus, which reduces ACh release as seen in AD patients, and nicotine from tobacco smoking can differentially affect LTD induction.

The absence of a2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of a2* nAChRs ("Chrna2"[superscript L9'S/L9'S] and "Chrna2"[superscript KO]) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the a2 subunit (encoded by the "Chrna2" gene) to make a hypersensitive nAChR. Using a dorsal hippocampus-dependent task of preexposure-dependent contextual fear conditioning, adolescent hypersensitive "Chrna2" [superscript L9'S/L9'S] male mice exhibited impaired learning and memory. The deficit was rescued by low-dose nicotine exposure. Electrophysiological studies demonstrated that hypersensitive a2 nAChRs potentiate acetylcholine-induced ion channel flux in oocytes and acute nicotine-induced facilitation of dorsal/intermediate CA1 hippocampal long-term potentiation in "Chrna2"[superscript L9'S/L9'S] mice. Adolescent male mice null for the a2 nAChR subunit exhibited a baseline deficit in learning that was not reversed by an acute dose of nicotine. These effects were not influenced by locomotor, sensory or anxiety-related measures. Our results demonstrated that a2* nAChRs influenced hippocampus-dependent learning and memory, as well as nicotine-facilitated CA1 hippocampal synaptic plasticity.

Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEls) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEls, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves ml receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of ml activation and Src. Thus, our results indicate not only that nAChRs, ACh, and ml receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. [ABSTRACT FROM AUTHOR]