RESUMO
RATIONALE: The use of electrical stimulation therapy to treat epilepsy is currently being studied in experimental animals and patients. Our study was designed to evaluate the effects of electrical stimulation applied in the thalamic reticular nucleus (TRN) on the development of pentylentetrazole-induced seizures. MATERIALS AND METHODS: Experiments were performed using male Wistar rats with electrodes stereotaxically implanted in the left TRN. Epidural EEG recording screws were implanted in the motor cortex for EEG recording. The rats were classified in seven groups: one sham group, four groups receiving either high- or low-frequency preemptive stimulation for either 10 or 60 minutes, and two groups receiving either high- or low-frequency responsive stimulation for ten minutes. All animals received a single dose of pentylentetrazole throughout five days. EEG recordings were obtained from the cortex and were evaluated to assess ictal behavior more than 45 to 90 minutes. RESULTS: Ten minutes of preemptive high-frequency stimulation in the TRN induced a significant decrease in seizure severity compared to 60 minutes of preemptive stimulation and ten minutes of responsive stimulation. Additionally, ten minutes of preemptive high-frequency stimulation protected against death as aftereffect of status epilepticus. The spike-wave complex frequency was not modified. CONCLUSIONS: These data could contribute to the characterization of the TRN in mediating the initiation and spreading of seizure activity and provide preclinical support for optimal parameters to use to obtain beneficial effects against convulsive activity.
Assuntos
Estimulação Encefálica Profunda/métodos , Pentilenotetrazol/toxicidade , Convulsões/induzido quimicamente , Convulsões/terapia , Núcleos Talâmicos , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Convulsões/fisiopatologia , Núcleos Talâmicos/fisiopatologia , Resultado do TratamentoRESUMO
Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca2+-dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Leptina/farmacologia , Neurônios/efeitos dos fármacos , Núcleos Talâmicos/citologia , Núcleos Talâmicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Temperatura Corporal/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Janus Quinase 2/metabolismo , Leptina/deficiência , Leptina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Transdução de Sinais/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais Sinápticos/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Tetrodotoxina/farmacologia , Tirfostinas/farmacologiaRESUMO
Through GABAergic fibers, globus pallidus (GP) coordinates basal ganglia global function. Electrical activity of GP neurons depends on their membrane properties and afferent fibers, including GABAergic fibers from striatum. In pathological conditions, abnormal electrical activity of GP neurons is associated with motor deficits. There is a GABAergic pathway from the GP to the reticular thalamic nucleus (RTn) whose contribution to RTn neurons electrical activity has received little attention. This fact called our attention because the RTn controls the overall information flow of thalamic nuclei to cerebral cortex. Here, we study the spontaneous electrical activity of RTn neurons recorded in vivo in anesthetized rats and under pharmacological activation or inhibition of the GP. We found that activation of GP predominantly diminishes the spontaneous RTn neurons firing rate and its inhibition increases their firing rate; however, both activation and inhibition of GP did not modified the burst index (BI) or the coefficient of variation (CV) of RTn neurons. Moreover, stimulation of striatum predominantly diminishes the spiking rate of GP cells and increases the spiking rate in RTn neurons without modifying the BI or CV in reticular neurons. Our data suggest a GP tight control over RTn spiking activity.
Assuntos
Potenciais de Ação , Corpo Estriado/fisiologia , Globo Pálido/fisiologia , Neurônios/fisiologia , Núcleos Talâmicos/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/administração & dosagem , GABAérgicos/administração & dosagem , Globo Pálido/efeitos dos fármacos , Ácido Glutâmico/administração & dosagem , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Núcleos Talâmicos/efeitos dos fármacos , Ácido gama-Aminobutírico/administração & dosagemRESUMO
Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 µM) and high (100 µM) 5-HT concentrations was observed in ventrobasal neurons from 5-HT2A -/- mice. In WT mice, only 100 µM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 µM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 µM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/- mice. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. Our findings suggest that both 5-HT1A , 5-HT2A and A1 receptors are present in pre-synaptic TRN terminals. 5-HT1A and A1 receptors would down-regulate adenylate cyclase, whereas 5-HT1A would also increase the probability of the opening of G-protein-activated inwardly rectifying K(+) channels (GIRK). Sustained opening of GIRK channels would hyperpolarize pre-synaptic terminals activating H-currents, resulting in less GABA release. 5-HT2A -would activate PLC and IP3 , increasing intracellular [Ca(2+) ] and thus facilitating GABA release.
Assuntos
Cafeína/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Núcleos Talâmicos/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Cloreto de Cádmio/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Receptor 5-HT2A de Serotonina/genética , Serotonina/farmacologia , Serotoninérgicos/farmacologia , Núcleos Talâmicos/metabolismo , Fosfolipases Tipo C/metabolismoRESUMO
BACKGROUND: Deep brain stimulation, specifically high-frequency stimulation (HFS), is an alternative and promising treatment for intractable epilepsies; however, the optimal targets are still unknown. The thalamic reticular nucleus (TRN) occupies a key position in the modulation of the cortico-thalamic and thalamo-cortical pathways. OBJECTIVE: We determined the efficacy of HFS in the TRN against tonic-clonic generalized seizures (TCGS) and status epilepticus (SE), which were induced by scheduled pentylenetetrazole (PTZ) injections. METHODS: Male Wistar rats were stereotactically implanted and assigned to three experimental groups: Control group, which received only PTZ injections; HFS-TRN group, which received HFS in the left TRN prior to PTZ injections; and HFS-Adj group, which received HFS in the left adjacent nuclei prior to PTZ injections. RESULTS: The HFS-TRN group reported a significant increase in the latency for development of TCGS and SE compared with the HFS-Adj and Control groups (P < 0.009). The number of PTZ-doses required for SE was also significantly increased (P < 0.001). Spectral analysis revealed a significant decrease in the frequency band from 0.5 Hz to 4.5 Hz of the left motor cortex in the HFS-TRN and HFS-Adj groups, compared to the Control group. Conversely, HFS-TRN provoked a significant increase in all frequency bands in the TRN. EEG asynchrony was observed during spike-wave discharges by HFS-TRN. CONCLUSION: These data indicate that HFS-TRN has an anti-epileptogenic effect and is able to modify seizure synchrony and interrupt abnormal EEG recruitment of thalamo-cortical and, indirectly, cortico-thalamic pathways.