RESUMO
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.
Assuntos
Nicotina , Receptores Nicotínicos , Animais , Feminino , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Gravidez , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismoRESUMO
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.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA1 Hipocampal/metabolismo , Fumar Cigarros , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Lactação , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Exposição Materna , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Knockout , Receptor Muscarínico M1/metabolismo , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Nicotínicos/metabolismoRESUMO
The absence of α2* 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 α2* nAChRs (Chrna2L9'S/L9'S and Chrna2KO) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the α2 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 Chrna2L9'S/L9'S male mice exhibited impaired learning and memory. The deficit was rescued by low-dose nicotine exposure. Electrophysiological studies demonstrated that hypersensitive α2 nAChRs potentiate acetylcholine-induced ion channel flux in oocytes and acute nicotine-induced facilitation of dorsal/intermediate CA1 hippocampal long-term potentiation in Chrna2L9'S/L9'S mice. Adolescent male mice null for the α2 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 α2* nAChRs influenced hippocampus-dependent learning and memory, as well as nicotine-facilitated CA1 hippocampal synaptic plasticity.
Assuntos
Hipocampo/fisiologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/patologia , Receptores Nicotínicos/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Ansiedade/genética , Ansiedade/patologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Medo/efeitos dos fármacos , Medo/fisiologia , Hipocampo/efeitos dos fármacos , Deficiências da Aprendizagem/tratamento farmacológico , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nicotina/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Oócitos , Receptores Nicotínicos/genética , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Xenopus laevisRESUMO
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.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Inibidores da Colinesterase/farmacologia , Agonistas Muscarínicos/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores de N-Metil-D-Aspartato/agonistas , Animais , Donepezila , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Indanos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Nicotina/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M1/agonistas , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Succinimidas/farmacologiaRESUMO
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.
Assuntos
Região CA1 Hipocampal/fisiologia , Interneurônios/fisiologia , Potenciação de Longa Duração/fisiologia , Transtornos da Memória , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Receptores Nicotínicos/fisiologia , Reconhecimento Psicológico/fisiologia , Memória Espacial/fisiologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Modelos Animais de Doenças , Feminino , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
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.
Assuntos
Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Neurônios/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Fatores Etários , Animais , Ansiedade/induzido quimicamente , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Nicotínicos/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
We examined the role of α7- and ß2-containing nicotinic acetylcholine receptors (nAChRs) in the induction of long-term potentiation (LTP). Theta-burst stimulation (TBS), mimicking the brain's naturally occurring theta rhythm, induced robust LTP in hippocampal slices from α7 and ß2 knockout mice. This suggests TBS is capable of inducing LTP without activation of α7- or ß2-containing nAChRs. However, when weak TBS was applied, the modulatory effects of nicotinic receptors on LTP induction became visible. We showed that during weak TBS, activation of α7 nAChRs occurs by the release of ACh, contributing to LTP induction. Additionally, bath-application of nicotine activated ß2-containing nAChRs to promote LTP induction. Despite predicted nicotine-induced desensitization, synaptically mediated activation of α7 nAChRs still occurs in the presence of nicotine and contributed to LTP induction. Optical recording of single-stimulation-evoked excitatory activity with a voltage-sensitive dye revealed enhanced excitatory activity in the presence of nicotine. This effect of nicotine was robust during high-frequency stimulation, and was accompanied by enhanced burst excitatory postsynaptic potentials. Nicotine-induced enhancement of excitatory activity was observed in slices from α7 knockout mice, but was absent in ß2 knockout mice. These results suggest that the nicotine-induced enhancement of excitatory activity is mediated by ß2-containing nAChRs, and is related to the nicotine-induced facilitation of LTP induction. Thus, our study demonstrates that the activation of α7- and ß2-containing nAChRs differentially facilitates LTP induction via endogenously released ACh and exogenous nicotine, respectively, in the hippocampal CA1 region of mice.
Assuntos
Acetilcolina/metabolismo , Região CA1 Hipocampal/citologia , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Aconitina/análogos & derivados , Aconitina/farmacologia , Análise de Variância , Animais , Animais Recém-Nascidos , Biofísica , Di-Hidro-beta-Eritroidina/farmacologia , Estimulação Elétrica , Técnicas In Vitro , Potenciação de Longa Duração/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Receptores Nicotínicos/deficiência , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/genética , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Hippocampal inhibitory interneurons have a central role in the control of network activity, and excitatory synapses that they receive express Hebbian and anti-Hebbian long-term potentiation (LTP). Because many interneurons in the hippocampus express nicotinic acetylcholine receptors (nAChRs), we explored whether exposure to nicotine promotes LTP induction in these interneurons. We focussed on a subset of interneurons in the stratum oriens/alveus that were continuously activated in the presence of nicotine due to the expression of non-desensitizing non-alpha7 nAChRs. We found that, in addition to alpha2 subunit mRNAs, these interneurons were consistently positive for somatostatin and neuropeptide Y mRNAs, and showed morphological characteristics of oriens-lacunosum moleculare cells. Activation of non-alpha7 nAChRs increased intracellular Ca(2+) levels at least in part via Ca(2+) entry through their channels. Presynaptic tetanic stimulation induced N-methyl-D-aspartate receptor-independent LTP in voltage-clamped interneurons at -70 mV when in the presence, but not absence, of nicotine. Intracellular application of a Ca(2+) chelator blocked LTP induction, suggesting the requirement of Ca(2+) signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca(2+) -induced Ca(2+) release from ryanodine-sensitive intracellular stores, and the L-type Ca(2+) channel blocker nifedipine. These results suggest that Ca(2+) entry through non-alpha7 nAChR channels is critical for LTP induction. Thus, nicotine affects hippocampal network activity by promoting LTP induction in oriens-lacunosum moleculare cells via continuous activation of non-alpha7 nAChRs.
Assuntos
Cálcio/metabolismo , Hipocampo/citologia , Interneurônios , Potenciação de Longa Duração/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/metabolismo , Quelantes/metabolismo , Ácido Egtázico/análogos & derivados , Ácido Egtázico/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Nifedipino/metabolismo , Técnicas de Patch-Clamp , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Rianodina/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
Rapid activation of nicotinic acetylcholine receptors (nAChRs) at various anatomical and cellular locations in the hippocampus differentially modulates the operation of hippocampal circuits. However, it is largely unknown how the continued presence of nicotine affects the normal operation of hippocampal circuits. Here, we used single and dual whole-cell recordings to address this question. We found that horizontally oriented interneurons in the stratum oriens/alveus continuously discharged action potentials in the presence of nicotine. In these interneurons, bath application of nicotine produced slow inward currents that were well maintained and inhibited by the non-alpha 7 antagonist dihydro-beta-erythroidine. Single-cell reverse transcription-polymerase chain reaction analysis showed that nicotine-responding interneurons were consistently positive for the alpha2 subunit mRNA. These observations suggest that in the presence of nicotine, a subset of interneurons in the stratum oriens/alveus are continuously excited due to the sustained activation of alpha2* nAChRs. These interneurons were synaptically connected to pyramidal cells, and nicotine increased inhibitory baseline currents at the synapses and suppressed phasic inhibition at the same synapses. Nicotine-induced inhibitory activity increased background noise and masked small phasic inhibition in pyramidal cells, originating from other interneurons in the stratum radiatum. Thus, the continued presence of nicotine alters the normal operation of hippocampal circuits by gating inhibitory circuits through activating a non-desensitizing alpha2 nAChR subtype on a distinct population of interneurons.
Assuntos
Hipocampo/citologia , Interneurônios/metabolismo , Isoformas de Proteínas/metabolismo , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Azetidinas/metabolismo , Azetidinas/farmacologia , Hipocampo/metabolismo , Potenciais Pós-Sinápticos Inibidores/fisiologia , Interneurônios/citologia , Interneurônios/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Nicotina/metabolismo , Nicotina/farmacologia , Técnicas de Patch-Clamp , Isoformas de Proteínas/genética , Subunidades Proteicas/genética , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/genéticaRESUMO
Evidence suggests that dopamine hyperfunction in schizophrenia blocks direct sensory information flow to CA1 pyramidal cells via the temporoammonic path. Owing to the high prevalence of smoking in schizophrenics, we examined whether nicotine modulates synaptic transmission in the temporoammonic path. Application of nicotine suppressed temporoammonic synaptic transmission as in the case of dopamine application. The suppressive effect of nicotine, however, disappeared in chronic nicotine-exposed hippocampi, suggesting the loss of nicotinic modulation of transmission in the temporoammonic path. In addition, the dopaminergic modulation of temporoammonic synaptic transmission decreased after chronic nicotine treatment. These observations suggest that chronic nicotine exposure affects the normal operation of hippocampal circuits.
Assuntos
Hipocampo/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Di-Hidro-beta-Eritroidina/farmacologia , Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos da radiação , Feminino , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Bloqueio Nervoso/métodos , Picrotoxina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
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 NRG1ß on NMDAR-mediated responses recorded from CA1 pyramidal cells in acute hippocampal slices. We found that NRG1ß, 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, NRG1ß 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. NRG1ß 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 NRG1ß 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.
Assuntos
Neuregulina-1/farmacologia , Plasticidade Neuronal/fisiologia , Nicotina/farmacologia , Receptores de N-Metil-D-Aspartato/fisiologia , Esquizofrenia , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
Recent studies suggest the involvement of the dorsal striatum in the advanced stages of drug addiction as well as motor functions. We investigated the effect of chronic nicotine treatment on GABAergic synaptic transmission in the striatum of mice. Intrastriatal stimulation evoked GABAA receptor-mediated polysynaptic inhibitory postsynaptic currents more frequently in medium-sized spiny projection neurons of mice treated chronically with nicotine (1 mg/kg, twice-daily subcutaneous injections for 10-15 days) than in those of PBS-treated mice. The multiphasic inhibitory postsynaptic currents consisted of monosynaptic early and polysynaptic, nicotinic acetylcholine receptor-mediated late components. Dihydro-beta-erythroidine, an antagonist of the non-alpha7nicotinic acetylcholine receptor, suppressed only the late inhibitory postsynaptic current. These results suggest that chronic nicotine treatment increases GABAergic input to projection neurons in the dorsal striatum.
Assuntos
Neostriado/fisiologia , Neurônios/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Ácido gama-Aminobutírico/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/citologia , Neostriado/efeitos dos fármacos , Técnicas de Patch-Clamp , Estimulação QuímicaRESUMO
Long-term potentiation (LTP) has a memory-like consolidation period during which it becomes progressively stabilized. However, it is unknown how the consolidation is achieved. The present study demonstrates that nicotine reverses stabilized LTP in the hippocampal CA1 region, providing the first evidence that consolidated LTP can be reversed. The nicotine-induced reversal appeared to work by reversing cellular processes involved in stabilizing LTP, as LTP was readily induced again after reversal. The effect of nicotine was mediated, in large part, via desensitization of alpha7 nicotinic acetylcholine receptors (nAChRs), as an alpha7 nAChR-selective antagonist mimicked the nicotine effect. A non-selective N-methyl-d-aspartate receptor (NMDAR) antagonist completely abolished the nicotine-induced reversal, whereas an NR2B-containing NMDAR-selective antagonist had no effect. Furthermore, both the protein phosphatase 1/protein phosphatase 2A inhibitor okadaic acid and the protein phosphatase 2B (calcineurin) inhibitor cyclosporin A blocked the nicotine-induced reversal. Taken together, our results suggest that the reversal of stabilized LTP depends on the activation of NR2A-containing NMDARs and dephosphorylation. Thus, the consolidation of LTP appears to be the interruption of signaling leading to NR2A-containing NMDAR-dependent activation of protein phosphatases, which can be circumvented by nicotine-induced signaling. LTP induced in chronic nicotine-treated hippocampi contained a component that is immune to reversal, and thus acute nicotine was no longer effective to reverse consolidated LTP. These results demonstrate the differential effects of acute and chronic nicotine exposure on the cellular processes that are potentially involved in learning and memory.
Assuntos
Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Aconitina/análogos & derivados , Aconitina/farmacologia , Análise de Variância , Animais , Di-Hidro-beta-Eritroidina/farmacologia , Relação Dose-Resposta à Radiação , Esquema de Medicação , Interações Medicamentosas , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Éteres Cíclicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Excitadores/efeitos da radiação , Hipocampo/fisiologia , Hipocampo/efeitos da radiação , Técnicas In Vitro , Potenciação de Longa Duração/efeitos da radiação , Masculino , Antagonistas Nicotínicos/farmacologia , Ácido Okadáico/farmacologia , Oxazóis/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Sinapses/efeitos dos fármacos , Ritmo Teta/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Actinas/efeitos dos fármacos , Animais , Caspase 3/efeitos dos fármacos , Depsipeptídeos/farmacologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidoresRESUMO
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.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Bicuculina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Antagonistas de Receptores de GABA-A/farmacologia , Hipocampo/citologia , Técnicas In Vitro , Masculino , Antagonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Valina/análogos & derivados , Valina/farmacologiaRESUMO
The nicotinic acetylcholine receptor (nAChR) alpha2 subunit was the first neuronal nAChR to be cloned. However, data for the distribution of alpha2 mRNA in the rodent exists in only a few studies. Therefore, we investigated the expression of alpha2 mRNA in the rat and mouse central nervous systems using nonradioactive in situ hybridization histochemistry. We detected strong hybridization signals in cell bodies located in the internal plexiform layer of the olfactory bulb, the interpeduncular nucleus of the midbrain, the ventral and dorsal tegmental nuclei, the median raphe nucleus of the pons, the ventral part of the medullary reticular nucleus, the ventral horn in the spinal cord of both rats and mice, and in a few Purkinje cells of rats, but not of mice. Cells that moderately express alpha2 mRNA were localized to the cerebral cortex layers V and VI, the subiculum, the oriens layer of CA1, the medial septum, the diagonal band complex, the substantia innominata, and the amygdala of both animals. They were also located in a few midbrain nuclei of rats, whereas in mice they were either few or absent in these areas. However, in the upper medulla oblongata alpha2 mRNA was expressed in several large neurons of the gigantocellular reticular nucleus and the raphe magnus nucleus of mice, but not of rats. The data obtained show that a similar pattern of alpha2 mRNA expression exists in both rats and mice, with the exception of a few regions, and provide the basis for cellular level analysis.
Assuntos
Encéfalo/metabolismo , RNA Mensageiro/metabolismo , Receptores Nicotínicos/metabolismo , Medula Espinal/metabolismo , Animais , Encéfalo/citologia , Feminino , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos , Neurônios/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Ratos , Receptores Nicotínicos/genética , Medula Espinal/citologia , Distribuição TecidualRESUMO
Long-term potentiation (LTP) in the hippocampal CA1 region is widely regarded to be the cellular substrate of learning and memory, and its induction critically depends on the activation of N-methyl-D-aspartate receptors (NMDARs). Nicotine reverses memory deficits caused by a lesion of the cholinergic system in animals. The mechanisms underlying this effect and the effect of nicotine on LTP after cholinergic degeneration are unknown. Here we show that cholinergic lesions impaired the induction of LTP, and nicotine reversed this effect and promoted the induction of LTP. The compensatory action of nicotine appears to be due to the enhancement of NMDAR responses mediated by nicotine-induced disinhibition of pyramidal cells. This may represent the cellular basis of nicotine-mediated cognitive enhancement observed in the presence of cholinergic deficits.
Assuntos
Fibras Colinérgicas/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Degeneração Neural/fisiopatologia , Inibição Neural/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
AIMS: Studying 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 METHODS: Extracellular field potential recordings were performed in hippocampal slices prepared from wild-type, α2, α7, and ß2 knockout (KO) mice. Effects of nicotine and nicotinic antagonists on LTD induction in wild-type, α2, α7, and ß2 KO mice were compared. KEY FINDINGS: Activation 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-ß-erythroidine, and was still observed in both α2 KO and ß2 KO mice. SIGNIFICANCE: This 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.
Assuntos
Acetilcolina/fisiologia , Nicotina/farmacologia , Receptores Nicotínicos/fisiologia , Animais , Hipocampo , Potenciação de Longa Duração/efeitos dos fármacos , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/fisiologiaRESUMO
Hippocampal CA1 pyramidal cells receive two major excitatory synaptic inputs via the Schaffer collateral (SC) and temporoammonic (TA) pathways. Nicotine promotes induction of long-term potentiation (LTP) in the SC path; however, it is not known whether the modulatory effect of nicotine on LTP induction is pathway-specific. Here we show that nicotine suppresses LTP induction in the TA path. Interestingly, these opposing effects of nicotine were absent or greatly reduced in alpha2 nicotinic acetylcholine receptor (nAChR)-knockout (KO) mice, suggesting that an alpha2-containing nAChR subtype mediates these effects. Optical imaging with a voltage-sensitive dye revealed significantly stronger membrane depolarization in the presence of nicotine in the SC path, facilitating spread of excitatory neural activity along both the somatodendritic and the CA1 proximodistal axes. These effects of nicotine were also absent in alpha2 nAChR-KO mice, suggesting that the enhanced optical signal is related to the nicotine-induced facilitation of LTP induction. In contrast, in the TA path nicotine terminated depolarization more quickly and increased the delayed hyperpolarization in the termination zone of the TA path input. These inhibitory effects of nicotine were absent in alpha2 nAChR-KO mice and, thus, most probably underlie the nicotine-induced suppression of LTP induction. Our results suggest that nicotine influences the local balance between excitation and inhibition, gates LTP, and directs information flow through the hippocampal circuits via the activation of alpha2* nAChRs. These effects of nicotine may represent the cellular basis of nicotine-mediated cognitive enhancement.
Assuntos
Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Nicotina/farmacologia , Células Piramidais/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Animais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Hipocampo/metabolismo , Potenciação de Longa Duração/genética , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Vias Neurais/metabolismo , Agonistas Nicotínicos/farmacologia , Técnicas de Cultura de Órgãos , Células Piramidais/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genéticaRESUMO
The use of nicotine via cigarette smoking forms long-lasting memories that are recalled in response to environmental cues associated with previous nicotine use. However, the changes in brain memory systems that underlie these long-lasting memories are not well understood. The N-methyl-D-aspartate receptor (NMDAR) is critical for long-lasting modifications of synapses. Here we show that in vivo nicotine exposure induces the enhancement of NR2B-containing NMDAR-mediated currents in the hippocampus, a brain region associated with the formation of memories. This nicotine effect is maintained during continued nicotine exposure and is accompanied by increased tyrosine phosphorylation of NR2B. Furthermore, long-term potentiation (LTP), which is considered to be a cellular substrate of learning and memory, induced in nicotine-exposed hippocampi contains a protein synthesis-independent long-lasting component. An NR2B-selective antagonist blocks a long-lasting component of LTP, but not LTP. These results suggest that exposure to nicotine provides conditions that promote the induction of long-lasting modifications of synapses, which may be involved in the formation of memories involving nicotine use.