RESUMO
Correct operation of neuronal networks depends on the interplay between synaptic excitation and inhibition processes leading to a dynamic state termed balanced network. In the spinal cord, balanced network activity is fundamental for the expression of locomotor patterns necessary for rhythmic activation of limb extensor and flexor muscles. After spinal cord lesion, paralysis ensues often followed by spasticity. These conditions imply that, below the damaged site, the state of balanced networks has been disrupted and that restoration might be attempted by modulating the excitability of sublesional spinal neurons. Because of the widespread expression of inhibitory GABAergic neurons in the spinal cord, their role in the early and late phases of spinal cord injury deserves full attention. Thus, an early surge in extracellular GABA might be involved in the onset of spinal shock while a relative deficit of GABAergic mechanisms may be a contributor to spasticity. We discuss the role of GABA A receptors at synaptic and extrasynaptic level to modulate network excitability and to offer a pharmacological target for symptom control. In particular, it is proposed that activation of GABA A receptors with synthetic GABA agonists may downregulate motoneuron hyperexcitability (due to enhanced persistent ionic currents) and, therefore, diminish spasticity. This approach might constitute a complementary strategy to regulate network excitability after injury so that reconstruction of damaged spinal networks with new materials or cell transplants might proceed more successfully.
Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Rede Nervosa/metabolismo , Receptores de GABA-A/metabolismo , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Neurônios GABAérgicos/fisiologia , Humanos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Rede Nervosa/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
Wistar Audiogenic Rats (WARs) are genetically susceptible to sound-induced seizures that start in the brainstem and, in response to repetitive stimulation, spread to limbic areas, such as hippocampus. Analysis of the distribution of interevent intervals of GABAergic inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal cells showed a monoexponential trend in Wistar rats, suggestive of a homogeneous population of synapses, but a biexponential trend in WARs. Based on this, we hypothesize that there are two populations of GABAergic synaptic release sites in CA1 pyramidal neurons from WARs. To address this hypothesis, we used a well-established neuronal computational model of a CA1 pyramidal neuron previously developed to replicate physiological properties of these cells. Our simulations replicated the biexponential trend only when we decreased the release frequency of synaptic currents by a factor of six in at least 40% of distal synapses. Our results suggest that almost half of the GABAergic synapses of WARs have a drastically reduced spontaneous release frequency. The computational model was able to reproduce the temporal dynamics of GABAergic inhibition that could underlie susceptibility to the spread of seizures.
Assuntos
Região CA1 Hipocampal/fisiopatologia , Epilepsia Reflexa/fisiopatologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Modelos Animais de Doenças , Ratos , Ratos WistarRESUMO
Motion detection represents one of the critical tasks of the visual system and has motivated a large body of research. However, it remains unclear precisely why the response of retinal ganglion cells (RGCs) to simple artificial stimuli does not predict their response to complex, naturalistic stimuli. To explore this topic, we use Motion Clouds (MC), which are synthetic textures that preserve properties of natural images and are merely parameterized, in particular by modulating the spatiotemporal spectrum complexity of the stimulus by adjusting the frequency bandwidths. By stimulating the retina of the diurnal rodent, Octodon degus with MC we show that the RGCs respond to increasingly complex stimuli by narrowing their adjustment curves in response to movement. At the level of the population, complex stimuli produce a sparser code while preserving movement information; therefore, the stimuli are encoded more efficiently. Interestingly, these properties were observed throughout different populations of RGCs. Thus, our results reveal that the response at the level of RGCs is modulated by the naturalness of the stimulus - in particular for motion - which suggests that the tuning to the statistics of natural images already emerges at the level of the retina.
Assuntos
Ritmo Circadiano/fisiologia , Percepção de Movimento/fisiologia , Movimento (Física) , Octodon/fisiologia , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Algoritmos , Animais , Potenciais Pós-Sinápticos Inibidores/fisiologia , Modelos Neurológicos , Movimento/fisiologia , Rede Nervosa/fisiologia , Estimulação Luminosa/métodos , Retina/citologia , Transmissão Sináptica/fisiologiaRESUMO
The morphological and functional development of inhibitory circuit in the anterior piriform cortex (aPC) during the first three postnatal weeks may be crucial for the development of odor preference learning in infant rodents. As first step toward testing this hypothesis, we examined the normal development of GABAergic synaptic transmission in the aPC of rat pups during the postnatal days (P) 5-8 and 14-17. Whole cell patch-clamp recordings of layer 2/3 (L2/3) aPC pyramidal cells revealed a significant increase in spontaneous (sIPSC) and miniature (mIPSC) inhibitory postsynaptic current frequencies and a decrease in mIPSC rise and decay-time constant at P14-P17. Moreover, as the development of neocortical inhibitory circuit can be driven by sensory experience, we recorded sIPSC and mIPSC onto L2/3 aPC pyramidal cells from unilateral naris-occluded animals. Early partial olfactory deprivation caused by naris occlusion do not affected the course of age-dependent increase IPSC frequency onto L2/3 aPC pyramidal cell. However, this age-dependent increase of sIPSC and mIPSC frequencies were lower on aPC pyramidal cells ipsilateral to the occlusion side. In addition, the age-dependent increase in sIPSC frequency and amplitude were more pronounced on aPC pyramidal cells contralateral to the occlusion. While mIPSC kinetics were not affected by age or olfactory deprivation, at P5-P8, the sIPSC decay-time constant on aPC pyramidal cells of both hemispheres of naris-occluded animals were significantly higher when compared to sham. These results demonstrated that the GABAergic synaptic transmission on the aPC changed during postnatal development by increasing inhibitory inputs on L2/3 pyramidal cells, with increment in frequency of both sIPSC and mIPSC and faster kinetics of mIPSC. Our data suggested that the maturation of GABAergic synaptic transmission was little affected by early partial olfactory deprivation. These results could contribute to unravel the mechanisms underlying the development of odor processing and olfactory preference learning.
Assuntos
Potenciais Pós-Sinápticos Inibidores/fisiologia , Córtex Piriforme/citologia , Córtex Piriforme/crescimento & desenvolvimento , Transmissão Sináptica/fisiologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Antagonistas de Receptores de GABA-A/farmacologia , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Ácido Cinurênico/farmacologia , Masculino , Técnicas de Patch-Clamp , Córtex Piriforme/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/efeitos da radiação , Ratos , Ratos Wistar , Privação Sensorial , Bloqueadores dos Canais de Sódio/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Tetrodotoxina/farmacologiaRESUMO
The ventral tegmental area (VTA) plays an important role in reward and motivational processes involved in drug addiction. Previous studies have shown that alpha1-adrenoreceptors (α1-AR) are primarily found pre-synaptically at this area. We hypothesized that GABA released onto VTA-dopamine (DA) cells is modulated by pre-synaptic α1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague-Dawley rats (28-50 days postnatal) using whole-cell voltage clamp technique. Phenylephrine (10 µM; α1-AR agonist) decreased the amplitude of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) evoked by electrical stimulation of afferent fibers (n = 7; p < 0.05). Prazosin (1 µM, α1-AR antagonist), blocked this effect. Paired-pulse ratios were increased by phenylephrine application (n = 13; p < 0.05) indicating a presynaptic site of action. Spontaneous IPSCs frequency but not amplitude, were decreased in the presence of phenylephrine (n = 7; p < 0.05). However, frequency or amplitude of miniature IPSCs were not changed (n = 9; p > 0.05). Phenylephrine in low Ca(2+) (1 mM) medium decreased IPSC amplitude (n = 7; p < 0.05). Chelerythrine (a protein kinase C inhibitor) blocked the α1-AR action on IPSC amplitude (n = 6; p < 0.05). Phenylephrine failed to decrease IPSCs amplitude in the presence of paxilline, a BK channel blocker (n = 7; p < 0.05). Taken together, these results demonstrate that α1-ARs at presynaptic terminals can modulate GABA release onto VTA-DA cells. Drug-induced changes in α1-AR could contribute to the modifications occurring in the VTA during the addiction process.
Assuntos
Neurônios Dopaminérgicos/fisiologia , Receptores Adrenérgicos alfa 1/metabolismo , Área Tegmentar Ventral/fisiologia , Ácido gama-Aminobutírico/metabolismo , Adrenérgicos/farmacologia , Animais , Benzofenantridinas/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Estimulação Elétrica , Indóis/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Masculino , Potenciais Pós-Sinápticos em Miniatura/efeitos dos fármacos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Técnicas de Patch-Clamp , Fenilefrina/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Prazosina/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/fisiologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in food intake and energy expenditure regulation. MC4R activation modifies neuronal activity but the molecular mechanisms by which this regulation occurs remain unclear. Here, we tested the hypothesis that MC4R activation regulates the activity of voltage-gated calcium channels and, as a consequence, synaptic activity. We also tested whether the proposed effect occurs in the amygdala, a brain area known to mediate the anorexigenic actions of MC4R signaling. Using the patch-clamp technique, we found that the activation of MC4R with its agonist melanotan II specifically inhibited 34.5 ± 1.5% of N-type calcium currents in transiently transfected HEK293 cells. This inhibition was concentration-dependent, voltage-independent and occluded by the Gαs pathway inhibitor cholera toxin. Moreover, we found that melanotan II specifically inhibited 25.9 ± 2.0% of native N-type calcium currents and 55.4 ± 14.4% of evoked inhibitory postsynaptic currents in mouse cultured amygdala neurons. In vivo, we found that the MC4R agonist RO27-3225 increased the marker of cellular activity c-Fos in several components of the amygdala, whereas the N-type channel blocker ω conotoxin GVIA increased c-Fos expression exclusively in the central subdivision of the amygdala. Thus, MC4R specifically inhibited the presynaptic N-type channel subtype, and this inhibition may be important for the effects of melanocortin in the central subdivision of the amygdala.
Assuntos
Tonsila do Cerebelo/fisiologia , Canais de Cálcio Tipo N/metabolismo , Terminações Pré-Sinápticas/fisiologia , Receptor Tipo 4 de Melanocortina/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Células Cultivadas , Fármacos do Sistema Nervoso Central/farmacologia , Toxina da Cólera/farmacologia , Células HEK293 , Humanos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Camundongos , Peptídeos/farmacologia , Peptídeos Cíclicos/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptor Tipo 4 de Melanocortina/agonistas , alfa-MSH/análogos & derivados , alfa-MSH/metabolismo , ômega-Conotoxina GVIA/farmacologiaRESUMO
Synchronization among neurons is thought to arise from the interplay between excitation and inhibition; however, the connectivity rules that contribute to synchronization are still unknown. We studied these issues in hippocampal CA1 microcircuits using paired patch clamp recordings and real time computing. By virtually connecting a model interneuron with two pyramidal cells (PCs), we were able to test the importance of connectivity in synchronizing pyramidal cell activity. Our results show that a circuit with a nonreciprocal connection between pyramidal cells and no feedback from PCs to the virtual interneuron produced the greatest level of synchronization and mutual information between PC spiking activity. Moreover, we investigated the role of intrinsic membrane properties contributing to synchronization where the application of a specific ion channel blocker, ZD7288 dramatically impaired PC synchronization. Additionally, background synaptic activity, in particular arising from NMDA receptors, has a large impact on the synchrony observed in the aforementioned circuit. Our results give new insights to the basic connection paradigms of microcircuits that lead to coordination and the formation of assemblies.
Assuntos
Hipocampo/citologia , Hipocampo/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Potenciais de Ação/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Células Piramidais/fisiologiaRESUMO
INTRODUCTION: Glycine and the gamma-aminobutyric acid are the principal inhibitory neurotransmitters in the vertebrate retina. The inhibitory action of glycine is mediated by the post-synaptic glycine receptor, a chloride-selective channel, constituted by three beta and two alpha subunits (alpha(1)-alpha(4)), which is antagonized by the alkaloid strychnine. In the retina, it is known that all alpha isoforms are expressed at the level of the inner synaptic layer with a very low colocalization. The glycine receptor formed by either alpha1 or alpha(3) shows rapid kinetics, whereas alpha(2) or alpha(4) receptors respond tonically. The use of transgenic mice has allowed the study of the different glycine receptor alpha subunits in the glycinegic neurotransmission of the mammalian retina. AIM: To describe the participation of the glycine receptor in the inhibitory neurotransmission particularly in the retina. DEVELOPMENT: In this review we describe the experiments that have allowed the localization and the involvement of the alpha subunit isoforms in specific transmission circuits of the vertebrate retina. CONCLUSIONS: The localization of the glycine receptor conformed by different isoforms of the alpha subunit in specific neuronal types, indicate the presence of glycinergic circuits that encode information differently in the retina.
Assuntos
Proteínas do Olho/fisiologia , Glicina/fisiologia , Potenciais Pós-Sinápticos Inibidores , Receptores de Glicina/fisiologia , Retina/fisiologia , Células Amácrinas/efeitos dos fármacos , Células Amácrinas/fisiologia , Animais , Cloretos/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Isoformas de Proteínas/fisiologia , Subunidades Proteicas , Receptores de Glicina/efeitos dos fármacos , Células Bipolares da Retina/efeitos dos fármacos , Células Bipolares da Retina/fisiologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/fisiologia , Estricnina/farmacologia , Transmissão Sináptica , Vertebrados/metabolismo , Vias Visuais/efeitos dos fármacos , Vias Visuais/fisiologiaRESUMO
In the mammalian inner ear, the gain control of auditory inputs is exerted by medial olivocochlear (MOC) neurons that innervate cochlear outer hair cells (OHCs). OHCs mechanically amplify the incoming sound waves by virtue of their electromotile properties while the MOC system reduces the gain of auditory inputs by inhibiting OHC function. How this process is orchestrated at the synaptic level remains unknown. In the present study, MOC firing was evoked by electrical stimulation in an isolated mouse cochlear preparation, while OHCs postsynaptic responses were monitored by whole-cell recordings. These recordings confirmed that electrically evoked IPSCs (eIPSCs) are mediated solely by α9α10 nAChRs functionally coupled to calcium-activated SK2 channels. Synaptic release occurred with low probability when MOC-OHC synapses were stimulated at 1 Hz. However, as the stimulation frequency was raised, the reliability of release increased due to presynaptic facilitation. In addition, the relatively slow decay of eIPSCs gave rise to temporal summation at stimulation frequencies >10 Hz. The combined effect of facilitation and summation resulted in a frequency-dependent increase in the average amplitude of inhibitory currents in OHCs. Thus, we have demonstrated that short-term plasticity is responsible for shaping MOC inhibition and, therefore, encodes the transfer function from efferent firing frequency to the gain of the cochlear amplifier.
Assuntos
Cóclea/citologia , Nervo Coclear/fisiologia , Células Ciliadas Auditivas/fisiologia , Inibição Neural/fisiologia , Sinapses/fisiologia , Estimulação Acústica , Animais , Animais Recém-Nascidos , Biofísica , Quelantes , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Estimulação Elétrica , Feminino , Glicinérgicos/farmacologia , Células Ciliadas Auditivas/efeitos dos fármacos , Técnicas In Vitro , Indóis/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Peptídeos/farmacologia , Antagonistas da Serotonina/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Estricnina/farmacologia , Sinapses/efeitos dos fármacos , Temperatura , Tetrodotoxina/farmacologia , Fatores de Tempo , TropizetronaRESUMO
Burst firing is ubiquitous in nervous systems and has been intensively studied in central pattern generators (CPGs). Previous works have described subtle intraburst spike patterns (IBSPs) that, despite being traditionally neglected for their lack of relation to CPG motor function, were shown to be cell-type specific and sensitive to CPG connectivity. Here we address this matter by investigating how a bursting motor neuron expresses information about other neurons in the network. We performed experiments on the crustacean stomatogastric pyloric CPG, both in control conditions and interacting in real-time with computer model neurons. The sensitivity of postsynaptic to presynaptic IBSPs was inferred by computing their average mutual information along each neuron burst. We found that details of input patterns are nonlinearly and inhomogeneously coded through a single synapse into the fine IBSPs structure of the postsynaptic neuron following burst. In this way, motor neurons are able to use different time scales to convey two types of information simultaneously: muscle contraction (related to bursting rhythm) and the behavior of other CPG neurons (at a much shorter timescale by using IBSPs as information carriers). Moreover, the analysis revealed that the coding mechanism described takes part in a previously unsuspected information pathway from a CPG motor neuron to a nerve that projects to sensory brain areas, thus providing evidence of the general physiological role of information coding through IBSPs in the regulation of neuronal firing patterns in remote circuits by the CNS.