RESUMEN
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.
Asunto(s)
Astrocitos/fisiología , Inhibición Neural/fisiología , Tálamo/fisiología , Percepción del Tacto/fisiología , Ácido gamma-Aminobutírico/fisiología , Familia de Aldehído Deshidrogenasa 1/metabolismo , Amina Oxidasa (conteniendo Cobre)/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/ultraestructura , Bestrofinas/biosíntesis , Bestrofinas/genética , Femenino , Antagonistas del GABA , Inmunohistoquímica , Potenciales Postsinápticos Inhibidores/fisiología , Macrólidos/farmacología , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica , Neuronas/metabolismo , Neuronas/fisiología , Técnicas de Placa-Clamp , Picrotoxina/farmacología , Cultivo Primario de Células , Piridazinas/farmacología , ARN Interferente Pequeño/farmacología , Retinal-Deshidrogenasa/metabolismo , Ácido gamma-Aminobutírico/biosíntesis , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Sleep abnormality often accompanies the impairment of cognitive function. Both rapid eye movement (REM) and non-REM (NREM) sleep have associated with improved memory performance. However, the role of composition in NREM sleep, consisting of light and deep NREM, for memory formation is not fully understood. We investigated how the dynamics of NREM sleep states influence memory consolidation. Thalamocortical (TC) neuron-specific phospholipase C ß4 (PLCß4) knockout (KO) increased the total duration of NREM sleep, consisting of destabilized light NREM and stabilized deep NREM. Surprisingly, the longer NREM sleep did not improve memory consolidation but rather impaired it in TC-specific PLCß4 KO mice. Memory function was positively correlated with the stability of light NREM and spindle activity occurring in maintained light NREM period. Our study suggests that a single molecule, PLCß4, in TC neurons is critical for tuning the NREM sleep states and thus affects sleep-dependent memory formation.
Asunto(s)
Consolidación de la Memoria/fisiología , Trastornos de la Memoria/enzimología , Proteínas del Tejido Nervioso/fisiología , Fosfolipasa C beta/fisiología , Fases del Sueño/fisiología , Tálamo/enzimología , Animales , Corteza Cerebral/enzimología , Condicionamiento Clásico/fisiología , Ritmo Delta/fisiología , Electroencefalografía , Electromiografía , Exones/genética , Conducta Exploratoria , Miedo/fisiología , Masculino , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/deficiencia , Neuronas/enzimología , Fosfolipasa C beta/deficiencia , Reconocimiento en Psicología , Eliminación de Secuencia , Sueño de Onda Lenta/fisiología , Factores de TiempoRESUMEN
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.
Asunto(s)
Anoctaminas/metabolismo , Calcio/farmacología , Células Receptoras Sensoriales/fisiología , Tálamo/fisiología , Adenoviridae , Animales , Anoctaminas/genética , Bestrofinas/genética , Bestrofinas/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Técnicas de Placa-Clamp , ortoaminobenzoatos/farmacologíaRESUMEN
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.