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This review focuses on the neuronal and circuit mechanisms involved in the generation of the theta (θ) rhythm and of its participation in behavior. Data have accumulated indicating that θ arises from interactions between medial septum-diagonal band of Broca (MS-DbB) and intra-hippocampal circuits. The intrinsic properties of MS-DbB and hippocampal neurons have also been shown to play a key role in θ generation. A growing number of studies suggest that θ may represent a timing mechanism to temporally organize movement sequences, memory encoding, or planned trajectories for spatial navigation. To accomplish those functions, θ and gamma (γ) oscillations interact during the awake state and REM sleep, which are considered to be critical for learning and memory processes. Further, we discuss that the loss of this interaction is at the base of various neurophatological conditions.
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[This corrects the article on p. 8 in vol. 11, PMID: 28203145.].
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According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca2+ spike and Ca2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information.
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Cholinergic mechanisms in the hippocampus regulate forms of synaptic plasticity linked with cognition and spatial navigation, but the underlying mechanisms remain largely unknown. Here, in rat hippocampal CA1 pyramidal cells under blockade of ionotropic glutamate receptors, we report that a single acetylcholine pulse and repeated depolarization activated a robust and enduring postsynaptic depolarization-induced enhancement of inhibition (DEI) that masked a presynaptic depolarization-induced suppression of inhibition (DSI). Increased cytosolic Ca2+ and M1-muscarinic receptor activation caused the rise in voltage-sensitive α5ßγ2-containing γ-aminobutyric acid type-A receptors that generated DEI. In summary, this muscarinic-mediated activity-dependent plasticity rapidly transfers depolarization effects on inhibition from presynaptic suppression or DSI to postsynaptic enhancement or DEI, a change potentially relevant in behavior.
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Acetilcolina/metabolismo , Región CA1 Hipocampal/metabolismo , Potenciales de la Membrana/fisiología , Inhibición Neural/fisiología , Células Piramidales/metabolismo , Animales , Región CA1 Hipocampal/efectos de los fármacos , Calcio/metabolismo , Citosol/efectos de los fármacos , Citosol/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Potenciales de la Membrana/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Técnicas de Placa-Clamp , Células Piramidales/efectos de los fármacos , Ratas Wistar , Receptor Cannabinoide CB1/metabolismo , Receptor Muscarínico M1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de GABA-A/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
Acetylcholine (ACh) regulates network operation in the hippocampus by controlling excitation and inhibition in rat CA1 pyramidal neurons (PCs), the latter through gamma-aminobutyric acid type-A receptors (GABA A Rs). Although, the enhancing effects of ACh on GABA A Rs have been reported (Dominguez et al., 2014, 2015), its role in regulating tonic GABAA inhibition has not been explored in depth. Therefore, we aimed at determining the effects of the activation of ACh receptors on responses mediated by synaptic and extrasynaptic GABAARs. Here, we show that under blockade of ionotropic glutamate receptors ACh, acting through muscarinic type 1 receptors, paired with post-synaptic depolarization induced a long-term enhancement of tonic GABA A currents ( t GABA A ) and puff-evoked GABA A currents ( p GABAA). ACh combined with depolarization also potentiated IPSCs (i.e., phasic inhibition) in the same PCs, without signs of interactions of synaptic responses with p GABAA and t GABAA, suggesting the contribution of two different GABAA receptor pools. The long-term enhancement of GABAA currents and IPSCs reduced the excitability of PCs, possibly regulating plasticity and learning in behaving animals.
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Acetylcholine (ACh) regulates forms of plasticity that control cognitive functions but the underlying mechanisms remain largely unknown. ACh controls the intrinsic excitability, as well as the synaptic excitation and inhibition of CA1 hippocampal pyramidal cells (PCs), cells known to participate in circuits involved in cognition and spatial navigation. However, how ACh regulates inhibition in function of postsynaptic activity has not been well studied. Here we show that in rat PCs, a brief pulse of ACh or a brief stimulation of cholinergic septal fibers combined with repeated depolarization induces strong long-term enhancement of GABAA inhibition (GABAA-LTP). Indeed, this enhanced inhibition is due to the increased activation of α5ßγ2 subunit-containing GABAA receptors by the GABA released. GABAA-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca(2+). In the absence of PC depolarization ACh triggered a presynaptic depolarization-induced suppression of inhibition (DSI), revealing that postsynaptic activity gates the effects of ACh from presynaptic DSI to postsynaptic LTP. These results provide key insights into mechanisms potentially linked with cognitive functions, spatial navigation, and the homeostatic control of abnormal hyperexcitable states.
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Acetilcolina/metabolismo , Región CA1 Hipocampal/fisiología , Plasticidad Neuronal/fisiología , Células Piramidales/fisiología , Receptores de GABA-A/metabolismo , Potenciales Sinápticos/fisiología , Animales , Calcio/metabolismo , Estimulación Eléctrica , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Receptor Muscarínico M1/metabolismoRESUMEN
The precise timing of pre-postsynaptic activity is vital for the induction of long-term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP-iLTD. The STDP-iLTD requires a postsynaptic Ca(2+) increase, a release of endocannabinoids (eCBs), the activation of type-1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP-iLTD is independent of the activation of nicotinic receptors, GABAB Rs and G protein-coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP-iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus.
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Región CA1 Hipocampal/citología , Endocannabinoides/metabolismo , Neuronas/fisiología , Receptores Muscarínicos/metabolismo , Transmisión Sináptica/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Colinérgicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Masculino , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions, but the underlying cellular mechanisms are largely unknown. We analyzed the effects of acetylcholine (ACh) on synaptic transmission and cell excitability in rat "barrel cortex" layer V (L5) pyramidal neurons in vitro. ACh through nicotinic and M1 muscarinic receptors enhanced excitatory postsynaptic currents and through nicotinic and M2 muscarinic receptors reduced inhibitory postsynaptic currents. These effects increased excitability and contributed to the generation of Ca(2+) spikes and bursts of action potentials (APs) when inputs in basal dendrites were stimulated. Ca(2+) spikes were mediated by activation of NMDA receptors (NMDARs) and L-type voltage-gated Ca(2+) channels. Additionally, we demonstrate in vivo that basal forebrain stimulation induced an atropine-sensitive increase of L5 AP responses evoked by vibrissa deflection, an effect mainly due to the enhancement of an NMDAR component. Therefore, ACh modified the excitatory/inhibitory balance and switched L5 pyramidal neurons to a bursting mode that caused a potent and sustained response enhancement with possible fundamental consequences for the function of the barrel cortex.
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Acetilcolina/metabolismo , Potenciales Postsinápticos Excitadores , Potenciales Postsinápticos Inhibidores , Neocórtex/fisiología , Células Piramidales/fisiología , Potenciales de Acción , Animales , Atropina/farmacología , Calcio/metabolismo , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Antagonistas Colinérgicos/farmacología , Dendritas/metabolismo , Dendritas/fisiología , Neocórtex/metabolismo , Células Piramidales/metabolismo , Ratas , Ratas Wistar , Receptor Muscarínico M1/antagonistas & inhibidores , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M2/antagonistas & inhibidores , Receptor Muscarínico M2/metabolismo , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Nicotínicos/metabolismo , Transmisión Sináptica , Vibrisas/fisiologíaRESUMEN
Long-term potentiation (LTP) has received attention because of its proposed role in learning and memory. Despite substantial effort the pre- or postsynaptic expression site of LTP remains unsettled. It has been proposed that LTP is expressed postsynaptically through the functional conversion of "silent synapses." We had shown that Schaffer collateral (SC) silent and "functional synapses," which lack and express AMPA receptors, respectively exhibit distinct transmitter release properties. Therefore the functional conversion of silent synapses with LTP should be associated with presynaptic modifications. We now show that the pairing-induced LTP at SC synapses is mediated by combined pre- and postsynaptic modifications involving the postsynaptic emergence of an AMPA response coupled with an enhanced glutamate release. BDNF replicates the changes associated with this LTP by activating TrkBRs, suggesting that the neurotrophin is required for the coordinated changes on both sides of the synaptic cleft.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Región CA1 Hipocampal/fisiología , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Receptor trkB/metabolismo , Receptores Presinapticos/fisiología , Sinapsis/fisiología , Animales , Fibras Colinérgicas/fisiología , Ácido Glutámico/metabolismo , Memoria/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/fisiología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
We had described a muscarinic-mediated long-term synaptic enhancement at Schaffer collateral synapses caused by the insertion of AMPARs in spines of rat hippocampal CA1 pyramidal neurons that requires Ca(2+) release from IP3-sensitive stores (Fernández de Sevilla et al., 2008). We now show that this AMPA-mediated LTP(IP3) is precisely matched by an amplification of NMDAR-mediated transmission. The enhanced AMPAR transmission involves SNARE protein activity and CaMKII activation. The amplification of NMDA transmission requires combined CaMKII, PKC, and SRC kinase activity without detectable surface incorporation of NMDARs, suggesting that changes in receptor properties mediate this process. The enhanced AMPAR- and NMDAR-mediated transmission markedly reduce the induction threshold of "Hebbian" LTP. We conclude that both modes of glutamatergic synaptic potentiation may play a critical functional role in the regulation of the learning machinery of the brain by adding flexibility to the demands of the hippocampal network.
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Región CA1 Hipocampal/fisiología , Potenciación a Largo Plazo/fisiología , Células Piramidales/fisiología , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/fisiología , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Espinas Dendríticas/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Ácido Glutámico/metabolismo , Técnicas In Vitro , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Proteína Quinasa C/metabolismo , Ratas , Ratas Wistar , Receptor Muscarínico M1/metabolismo , Proteínas SNARE/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
The cellular mechanisms that mediate spike timing-dependent plasticity (STDP) are largely unknown. We studied in vitro in CA1 pyramidal neurons the contribution of AMPA and N-methyl-d-aspartate (NMDA) components of Schaffer collateral (SC) excitatory postsynaptic potentials (EPSPs; EPSP(AMPA) and EPSP(NMDA)) and of the back-propagating action potential (BAP) to the long-term potentiation (LTP) induced by a STDP protocol that consisted in pairing an EPSP and a BAP. Transient blockade of EPSP(AMPA) with 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX) during the STDP protocol prevented LTP. Contrastingly LTP was induced under transient inhibition of EPSP(AMPA) by combining SC stimulation, an imposed EPSP(AMPA)-like depolarization, and BAP or by coupling the EPSP(NMDA) evoked under sustained depolarization (approximately -40 mV) and BAP. In Mg(2+)-free solution EPSP(NMDA) and BAP also produced LTP. Suppression of EPSP(NMDA) or BAP always prevented LTP. Thus activation of NMDA receptors and BAPs are needed but not sufficient because AMPA receptor activation is also obligatory for STDP. However, a transient depolarization of another origin that unblocks NMDA receptors and a BAP may also trigger LTP.
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Potenciales de Acción/fisiología , Región CA1 Hipocampal/fisiología , Potenciación a Largo Plazo/fisiología , Células Piramidales/fisiología , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Región CA1 Hipocampal/efectos de los fármacos , Fármacos del Sistema Nervioso Central/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Magnesio/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Técnicas de Placa-Clamp , Células Piramidales/efectos de los fármacos , Ratas , Ratas Wistar , Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
Cholinergic-glutamatergic interactions influence forms of synaptic plasticity that are thought to mediate memory and learning. We tested in vitro the induction of long-lasting synaptic enhancement at Schaffer collaterals by acetylcholine (ACh) at the apical dendrite of CA1 pyramidal neurons and in vivo by stimulation of cholinergic afferents. In vitro ACh induced a Ca2+ wave and synaptic enhancement mediated by insertion of AMPA receptors in spines. Activation of muscarinic ACh receptors (mAChRs) and Ca2+ release from inositol 1,4,5-trisphosphate (IP3)-sensitive stores were required for this synaptic enhancement that was insensitive to blockade of NMDA receptors and also triggered by IP3 uncaging. Activation of cholinergic afferents in vivo induced an analogous atropine-sensitive synaptic enhancement. We describe a novel form of synaptic enhancement (LTP(IP3)) that is induced in vitro and in vivo by activation of mAChRs. We conclude that Ca2+ released from postsynaptic endoplasmic reticulum stores is the critical event in the induction of this unique form of long-lasting synaptic enhancement.
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Acetilcolina/fisiología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Potenciación a Largo Plazo/fisiología , Células Piramidales/metabolismo , Acetilcolina/farmacología , Animales , Calcio/metabolismo , Colinérgicos/farmacología , Femenino , Receptores de Inositol 1,4,5-Trifosfato/agonistas , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Células Piramidales/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Using spike-timing-dependent plasticity (STDP) protocols that consist of pairing an EPSP and a postsynaptic backpropagating action potential (BAP), we investigated the contribution of the changes in EPSP waveform induced by the slow Ca2+-dependent K+-mediated afterhyperpolarization (sAHP) in the regulation of long-term potentiation (LTP). The "temporal window" between Schaffer collateral EPSPs and BAPs in CA1 pyramidal neurons required to induce LTP was narrowed by a reduction of the amplitude and decay time constant of the EPSP, which could be reversed with cyclothiazide. The EPSP changes were caused by the increased conductance induced by activation of the sAHP. Therefore, the EPSP waveform and its regulation by the sAHP are central in determining the duration of the temporal window for STDP, thus providing a possible dynamic regulatory mechanism for the encoding of cognitive processes.
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Potenciales de Acción/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Agonistas Adrenérgicos beta/farmacología , Animales , Animales Recién Nacidos , Calcio/metabolismo , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Hipocampo/citología , Técnicas In Vitro , Isoproterenol/farmacología , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Pyramidal neuron dendrites express voltage-gated conductances that control synaptic integration and plasticity, but the contribution of the Ca(2+)-activated K(+)-mediated currents to dendritic function is not well understood. Using dendritic and somatic recordings in rat hippocampal CA1 pyramidal neurons in vitro, we analyzed the changes induced by the slow Ca(2+)-activated K(+)-mediated afterhyperpolarization (sAHP) generated by bursts of action potentials on excitatory postsynaptic potentials (EPSPs) evoked at the apical dendrites by perforant path-Schaffer collateral stimulation. Both the amplitude and decay time constants of EPSPs (tau(EPSP)) were reduced by the sAHP in somatic recordings. In contrast, the dendritic EPSP amplitude remained unchanged, whereas tau(EPSP) was reduced. Temporal summation was reduced and spatial summation linearized by the sAHP. The amplitude of the isolated N-methyl-D-aspartate component of EPSPs (EPSP(NMDA)) was reduced, whereas tau(NMDA) was unaffected by the sAHP. In contrast, the sAHP did not modify the amplitude of the isolated EPSP(AMPA) but reduced tau(AMPA) both in dendritic and somatic recordings. These changes are attributable to a conductance increase that acted mainly via a selective "shunt" of EPSP(NMDA) because they were absent under voltage clamp, not present with imposed hyperpolarization simulating the sAHP, missing when the sAHP was inhibited with isoproterenol, and reduced under block of EPSP(NMDA). EPSPs generated at the basal dendrites were similarly modified by the sAHP, suggesting both a somatic and apical dendritic location of the sAHP channels. Therefore the sAHP may play a decisive role in the dendrites by regulating synaptic efficacy and temporal and spatial summation.
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Agonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/citología , N-Metilaspartato/farmacología , Células Piramidales/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacología , Animales , Animales Recién Nacidos , Calcio/metabolismo , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Técnicas In Vitro , Isoproterenol/farmacología , Técnicas de Placa-Clamp/métodos , Células Piramidales/citología , Células Piramidales/fisiología , Ratas , Ratas Wistar , Factores de Tiempo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca(2+)-activated K(+)-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg(2+)-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO(4) reduced burst frequency. Block of GABA(A-B) inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.
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Señalización del Calcio/fisiología , Epilepsia/fisiopatología , Hipocampo/fisiopatología , Canales de Potasio Calcio-Activados/fisiología , Células Piramidales/fisiología , 4-Aminopiridina/farmacología , Animales , Señalización del Calcio/efectos de los fármacos , Cesio/farmacología , Quelantes/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Estimulación Eléctrica , Electrofisiología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Calcio-Activados/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Ratas , Ratas Wistar , Ritmo Teta/efectos de los fármacosRESUMEN
Somatosensory information, conveyed through the gracilis nucleus (GN), is regulated by descending corticofugal (CF) glutamatergic fibers. In addition, the GN receives cholinergic inputs with still unclear source and functional significance. Using both the in vitro slice and intracellular recording with sharp and patch electrodes and in vivo extracellular single-unit recordings, we analyzed the effects of activation of cholinergic receptors on synaptic, intrinsic, and functional properties of rat GN neurons. The cholinergic agonist carbamilcholine-chloride [carbachol (CCh); 1-10 microM] in vitro (1) induced presynaptic inhibition of EPSPs evoked by both dorsal column and CF stimulation, (2) increased postsynaptic excitability, and (3) amplified the spike output of GN neurons. The inhibition by atropine (1 microM) and pirenzepine (10 microM) of all presynaptic and postsynaptic effects of CCh suggests actions through muscarinic M1 receptors. The above effects were insensitive to nicotinic antagonists. We searched the anatomical origin of the cholinergic projection to the GN throughout the hindbrain and forebrain, and we found that the cholinergic fibers originated mainly in the pontine reticular nucleus (PRN). Electrical stimulation of the PRN amplified sensory responses in the GN in vivo, an effect prevented by topical application of atropine. Our results demonstrate for the first time that cholinergic agonists induce both presynaptic and postsynaptic effects on GN neurons and suggest an important regulatory action of inputs from cholinergic neuronal groups in the pontine reticular formation in the functional control of somatosensory information flow in the GN.
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Colinérgicos/farmacología , Cuerpos Geniculados/fisiología , Transmisión Sináptica/fisiología , Animales , Cloruro de Calcio/farmacología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Cuerpos Geniculados/efectos de los fármacos , Técnicas In Vitro , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacosRESUMEN
Recent evidence suggests that functional and silent synapses are not only postsynaptically different but also presynaptically distinct. The presynaptic differences may be of functional importance in memory formation because a proposed mechanism for long-term potentiation is the conversion of silent synapses into functional ones. However, there is little direct experimentally evidence of these differences. We have investigated the transmitter release properties of functional and silent Schaffer collateral synapses and show that on the average functional synapses displayed a lower percentage of failures and higher excitatory postsynaptic current (EPSC) amplitudes than silent synapses at +60 mV. Moreover, functional but not silent synapses show paired-pulse facilitation (PPF) at +60 mV and thus presynaptic short-term plasticity will be distinct in the two types of synapse. We examined whether intraterminal endoplasmic reticulum Ca2+ stores influenced the release properties of these synapses. Ryanodine (100 microM) and thapsigargin (1 microM) increased the percentage of failures and decreased both the EPSC amplitude and PPF in functional synapses. Caffeine (10 mM) had the opposite effects. In contrast, silent synapses were insensitive to both ryanodine and caffeine. Hence we have identified differences in the release properties of functional and silent synapses, suggesting that synaptic terminals of functional synapses express regulatory molecular mechanisms that are absent in silent synapses.
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Hipocampo/citología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Neurotransmisores/metabolismo , Sinapsis/fisiología , Animales , Cafeína/farmacología , Relación Dosis-Respuesta en la Radiación , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Agonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Excitadores/efectos de la radiación , Técnicas In Vitro , N-Metilaspartato/farmacología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/efectos de la radiación , Neuronas/efectos de los fármacos , Neuronas/efectos de la radiación , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Wistar , Rianodina/farmacología , Sinapsis/clasificación , Sinapsis/efectos de los fármacos , Sinapsis/efectos de la radiación , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
Ca2+-activated K+ currents with medium (mI(AHP)) and slow (sI(AHP)) kinetics, that mediate the post-spike medium and slow after-hyperpolarization (AHP), respectively, play critical roles in regulating neuronal excitability and the spread of epileptiform activity and could provide new therapeutic targets for the management of epileptic patients. We tested if the enhancement of the mI(AHP) by 1-ethyl-2-benzimidazolinone (EBIO) could suppress epileptiform activity in two in vitro models of epileptogenesis induced in CA3 hippocampal pyramidal neurons by superfusion with 4-AP- and kainate-Mg2+-free solutions. Both interictal- and ictal-like epileptiform activities were reversibly suppressed by EBIO concentrations between 200 microM and 1 mM. EBIO predominantly acted by a strong reduction of excitability via an increase (approximately 450%) of the mI(AHP), without changing the sI(AHP). Glutamatergic excitatory synaptic transmission was also diminished (approximately 50%) by 1 mM EBIO. In contrast, EBIO concentrations <400 microM had no effect on synaptic excitation, consistent with a lesser sensitivity to the drug than the mI(AHP). Apamine (100 nM), a toxin that specifically inhibits the mI(AHP), rapidly and reversibly antagonized the blocking effects of EBIO on epileptiform activity. Our results suggest that manipulations that enhance the mI(AHP) may prove adequate in the treatment of epilepsies; they also suggest that an abnormal down regulation of the mI(AHP) may be a key factor in the genesis of hyperexcitable states.
Asunto(s)
Anticonvulsivantes/farmacología , Bencimidazoles/farmacología , Agonistas de los Canales de Calcio/farmacología , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Algoritmos , Animales , Apamina/farmacología , Estimulación Eléctrica , Electrofisiología , Epilepsia/fisiopatología , Agonistas de Aminoácidos Excitadores/farmacología , Hipocampo/fisiopatología , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , N-Metilaspartato/farmacología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Calcio-Activados/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Ratas , Canales de Potasio de Pequeña Conductancia Activados por el Calcio , Transmisión Sináptica/efectos de los fármacosRESUMEN
The role of adenosine triphosphate (ATP) as a neurotransmitter and extracellular diffusible messenger has recently received considerable attention because of its possible participation in the regulation of synaptic plasticity. However, the possible contribution of extracellular ATP in maintaining and regulating synaptic efficacy during intracellular ATP depletion is understudied. We tested the effects of extracellular ATP on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by Schaffer collateral stimulation. In the absence of intracellular ATP, EPSC rundown was neutralized when a low concentration of ATP (1 microm) was added to the extracellular solution. Adenosine and ATP analogues did not prevent the EPSC rundown. The P(2) antagonists piridoxal-5'-phosphate-azophenyl 2',4'-disulphonate (PPADS) and reactive blue-2, and the P(1) adenosine receptor antagonist 8-cyclopentyltheophylline (CPT) had no detectable effects in cells depleted of ATP. However, the protective action of extracellular ATP on synaptic efficacy was blocked by extracellular application of the protein kinase inhibitors K252b and staurosporine. In contrast, K252b and staurosporine per se did not interfere with synaptic transmission in ATP loaded cells. Without intracellular ATP, bath-applied caffeine induced a transient (< 35 min) EPSC potentiation that was transformed into a persistent long-term potentiation (> 80 min) when 1 microm ATP was added extracellularly. An increased probability of transmitter release paralleled the long-term potentiation induced by caffeine, suggesting that it originated presynaptically. Therefore, we conclude that extracellular ATP may operate to maintain and regulate synaptic efficacy and plasticity in conditions of abnormal intracellular ATP depletion by phosphorylation of a surface protein substrate via activation of ecto-protein kinases.