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2.
Neuron ; 108(4): 691-706.e10, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32905785

RESUMO

Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.


Assuntos
Astrócitos/fisiologia , Inibição Neural/fisiologia , Tálamo/fisiologia , Percepção do Tato/fisiologia , Ácido gama-Aminobutírico/fisiologia , Família Aldeído Desidrogenase 1/metabolismo , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/ultraestrutura , Bestrofinas/biossíntese , Bestrofinas/genética , Feminino , Antagonistas GABAérgicos , Imuno-Histoquímica , Potenciais Pós-Sinápticos Inibidores/fisiologia , Macrolídeos/farmacologia , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Cultura Primária de Células , Piridazinas/farmacologia , RNA Interferente Pequeno/farmacologia , Retinal Desidrogenase/metabolismo , Ácido gama-Aminobutírico/biossíntese , Ácido gama-Aminobutírico/farmacologia
3.
Mol Brain ; 9(1): 100, 2016 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-27998287

RESUMO

The transition from wakefulness to a nonrapid eye movement (NREM) sleep state at the onset of sleep involves a transition from low-voltage, high-frequency irregular electroencephalography (EEG) waveforms to large-amplitude, low-frequency EEG waveforms accompanying synchronized oscillatory activity in the thalamocortical circuit. The thalamocortical circuit consists of reciprocal connections between the thalamus and cortex. The cortex sends strong excitatory feedback to the thalamus, however the function of which is unclear. In this study, we investigated the role of the thalamic metabotropic glutamate receptor 1 (mGluR1)-phospholipase C ß4 (PLCß4) pathway in sleep control in PLCß4-deficient (PLCß4-/-) mice. The thalamic mGluR1-PLCß4 pathway contains synapses that receive corticothalamic inputs. In PLCß4-/- mice, the transition from wakefulness to the NREM sleep state was stimulated, and the NREM sleep state was stabilized, which resulted in increased NREM sleep. The power density of delta (δ) waves increased in parallel with the increased NREM sleep. These sleep phenotypes in PLCß4-/- mice were consistent in TC-restricted PLCß4 knockdown mice. Moreover, in vitro intrathalamic oscillations were greatly enhanced in the PLCß4-/- slices. The results of our study showed that thalamic mGluR1-PLCß4 pathway was critical in controlling sleep architecture.


Assuntos
Fosfolipase C beta/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sono/fisiologia , Tálamo/metabolismo , Animais , Córtex Cerebral/fisiologia , Ritmo Delta/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipase C beta/deficiência , Tálamo/fisiologia
4.
Nat Commun ; 7: 13791, 2016 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-27991499

RESUMO

Neuronal firing patterns, which are crucial for determining the nature of encoded information, have been widely studied; however, the molecular identity and cellular mechanisms of spike-frequency adaptation are still not fully understood. Here we show that spike-frequency adaptation in thalamocortical (TC) neurons is mediated by the Ca2+-activated Cl- channel (CACC) anoctamin-2 (ANO2). Knockdown of ANO2 in TC neurons results in significantly reduced spike-frequency adaptation along with increased tonic spiking. Moreover, thalamus-specific knockdown of ANO2 increases visceral pain responses. These results indicate that ANO2 contributes to reductions in spike generation in highly activated TC neurons and thereby restricts persistent information transmission.


Assuntos
Anoctaminas/metabolismo , Cálcio/farmacologia , Células Receptoras Sensoriais/fisiologia , Tálamo/fisiologia , Adenoviridae , Animais , Anoctaminas/genética , Bestrofinas/genética , Bestrofinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Técnicas de Patch-Clamp , ortoaminobenzoatos/farmacologia
5.
Proc Natl Acad Sci U S A ; 110(50): 20266-71, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24282303

RESUMO

T-type Ca(2+) channels in thalamocortical (TC) neurons have long been considered to play a critical role in the genesis of sleep spindles, one of several TC oscillations. A classical model for TC oscillations states that reciprocal interaction between synaptically connected GABAergic thalamic reticular nucleus (TRN) neurons and glutamatergic TC neurons generates oscillations through T-type channel-mediated low-threshold burst firings of neurons in the two nuclei. These oscillations are then transmitted from TC neurons to cortical neurons, contributing to the network of TC oscillations. Unexpectedly, however, we found that both WT and KO mice for CaV3.1, the gene for T-type Ca(2+) channels in TC neurons, exhibit typical waxing-and-waning sleep spindle waves at a similar occurrence and with similar amplitudes and episode durations during non-rapid eye movement sleep. Single-unit recording in parallel with electroencephalography in vivo confirmed a complete lack of burst firing in the mutant TC neurons. Of particular interest, the tonic spike frequency in TC neurons was significantly increased during spindle periods compared with nonspindle periods in both genotypes. In contrast, no significant change in burst firing frequency between spindle and nonspindle periods was noted in the WT mice. Furthermore, spindle-like oscillations were readily generated within intrathalamic circuits composed solely of TRN and TC neurons in vitro in both the KO mutant and WT mice. Our findings call into question the essential role of low-threshold burst firings in TC neurons and suggest that tonic firing is important for the generation and propagation of spindle oscillations in the TC circuit.


Assuntos
Ondas Encefálicas/fisiologia , Modelos Neurológicos , Neurônios/metabolismo , Periodicidade , Sono/fisiologia , Tálamo/metabolismo , Animais , Canais de Cálcio Tipo T/genética , Eletroencefalografia , Camundongos , Camundongos Knockout
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